Amide compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use

ABSTRACT

Amide compounds that modulate and/or inhibit the activity of certain protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating tyrosine kinase signal transduction in order to modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.

[0001] This applications claims the benefit of U.S. ProvisionalApplication Serial No. 60/177,059, filed Jan. 21, 2000, the contents ofwhich are hereby incorporated by reference herein.

FIELD OF THE INVENTION

[0002] This invention is directed to amide compounds that mediate and/orinhibit the activity of certain protein kinases, and to pharmaceuticalcompositions containing such compounds. The invention is also directedto the therapeutic or prophylactic use of such compounds andcompositions, and to methods of treating cancer as well as other diseasestates associated with unwanted angiogenesis and/or cellularproliferation, by administering effective amounts of such compounds.

BACKGROUND OF THE INVENTION

[0003] Protein kinases are a family of enzymes that catalyzephosphorylation of the hydroxyl group of specific tyrosine, serine, orthreonine residues in proteins. Typically, such phosphorylationdramatically perturbs the function of the protein, and thus proteinkinases are pivotal in the regulation of a wide variety of cellularprocesses, including metabolisim, cell proliferation, celldifferentiation, and cell survival. Of the many different cellularfunctions in which the activity of protein kinases is known to berequired, some processes represent attractive targets for therapeuticintervention for certain disease states. Two examples are angiogenesisand cell-cycle control, in which protein kinases play a pivotal role;these processes are essential for the growth of solid tumors as well asfor other diseases.

[0004] Angiogenesis is the mechanism by which new capillaries are formedfrom existing vessels. When required, the vascular system has thepotential to generate new capillary networks in order to maintain theproper functioning of tissues and organs. In the adult, however,angiogenesis is fairly limited, occurring only in the process of woundhealing and neovascularization of the endometrium during menstruation.See Merenmies, J., Parada, L. F., Henkemeyer, M., Cell Growth &Differentiation, 8, 3-10 (1997). On the other hand, unwantedangiogenesis is a hallmark of several diseases, such as retinopathies,psoriasis, rheumatoid arthritis, age-related macular degeneneration, andcancer (solid tumors). Folkman, Nature Med., 1, 27-31 (1995). Proteinkinases which have been shown to be involved in the angiogenic processinclude three members of the growth factor receptor tyrosine kinasefamily: VEGF-R2 (vascular endothelial growth factor receptor 2, alsoknown as KDR (kinase insert domain receptor) and as FLK-1); FGF-R(fibroblast growth factor receptor); and TEK (also known as Tie-2).

[0005] VEGF-R2, which is selectively expressed on endothelial cells,binds the potent angiogenic growth factor VEGF and mediates thesubsequent signal transduction through activation of its intracellularkinase activity. Thus, it is expected that direct inhibition of thekinase activity of VEGF-R2 will result in the reduction of angiogenesiseven in the presence of exogenous VEGF (see Strawn et al., CancerResearch, 56, 3540-3545 (1996)), as has been shown with mutants ofVEGF-R2 which fail to mediate signal transduction. Millauer et al.,Cancer Research, 56, 1615-1620 (1996). Furthermore, VEGF-R2 appears tohave no function in the adult beyond that of mediating the angiogenicactivity of VEGF. Therefore, a selective inhibitor of the kinaseactivity of VEGF-R2 would be expected to exhibit little toxicity.

[0006] Similarly, FGF-R binds the angiogenic growth factors aFGF andbFGF and mediates subsequent intracellular signal transduction.Recently, it has been suggested that growth factors such as bFGF mayplay a critical role in inducing angiogenesis in solid tumors that havereached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928(1997). Unlike VEGF-R2, however, FGF-R is expressed in a number ofdifferent cell types throughout the body and may or may not playimportant roles in other normal physiological processes in the adult.Nonetheless, systemic administration of a small molecule inhibitor ofthe kinase activity of FGF-R has been reported to block bFGF-inducedangiogenesis in mice without apparent toxicity. Mohammad et al., EMBOJournal, 17, 5996-5904 (1998).

[0007] TEK (also known as Tie-2) is another receptor tyrosine kinaseselectively expressed on endothelial cells which has been shown to playa role in angiogenesis. The binding of the factor angiopoietin-1 resultsin autophosphorylation of the kinase domain of TEK and results in asignal transduction process which appears to mediate the interaction ofendothelial cells with peri-endothelial support cells, therebyfacilitating the maturation of newly formed blood vessels. The factorangiopoietin-2, on the other hand, appears to antagonize the action ofangiopoietin-1 on TEK and disrupts angiogenesis. Maisonpierre et al.,Science, 277, 55-60 (1997).

[0008] As a result of the above-described developments, it has beenproposed to treat angiogenesis by the use of compounds inhibiting thekinase activity of VEGF-R2, FGF-R, and/or TEK. For example, WIPOInternational Publication No. WO 97/34876 discloses certain cinnolinederivatives that are inhibitors of VEGF-R2, which may be used for thetreatment of disease states associated with abnormal angiogenesis and/orincreased vascular permeability such as cancer, diabetes, psoriosis,rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronicnephropathies, atheroma, arterial restinosis, autoimmune diseases, acuteinflammation and ocular diseases with retinal vessel proliferation. Twodocuments described hereinafter disclose certain amide derivatives butdo not disclose or teach that any of the compounds may be used formodulating or inhibiting the activity of protein kinases: WIPOInternational Publication No. WO 97/03967; and WIPO InternationalPublication No. WO 96/23783.

[0009] In addition to its role in angiogenesis, protein kinases alsoplay a crucial role in cell-cycle control. Uncontrolled cellproliferation is the insignia of cancer. Cell proliferation in responseto various stimuli is manifested by a de-regulation of the cell divisioncycle, the process by which cells multiply and divide. Tumor cellstypically have damage to the genes that directly or indirectly regulateprogression through the cell division cycle.

[0010] Cyclin-dependent kinases (CDKs) are serine-threonine proteinkinases that play critical roles in regulating the transitions betweendifferent phases of the cell-cycle, such as the progression from aquiescent stage in G₁ (the gap between mitosis and the onset of DNAreplication for a new round of cell division) to S (the period of activeDNA synthesis), or the progression from G₂ to M phase, in which activemitosis and cell-division occurs. See, e.g., the articles compiled inScience, 274, 1643-1677 (1996). CDK complexes are formed throughassociation of a regulatory cyclin subunit (e.g., cyclin A, B 1, B2, D1,D2, D3, and E) and a catalytic kinase subunit (e.g., cdc2 (CDK1), CDK2,CDK4, CDK5, and CDK6). As the name implies, the CDKs display an absolutedependence on the cyclin subunit in order to phosphorylate their targetsubstrates, and different kinase/cyclin pairs function to regulateprogression through specific phases of the cell-cycle.

[0011] It is CDK4 complexed to the D cyclins that plays a critical partin initiating the cell-division cycle from a resting or quiescent stageto one in which cells become committed to cell division. Thisprogression is subject to a variety of growth regulatory mechanisms,both negative and positive. Aberrations in this control system,particularly those that affect the function of CDK4, have beenimplicated in the advancement of cells to the highly proliferative statecharacteristic of malignancies, particularly familial melanomas,esophageal carcinomas, and pancreatic cancers. See, e.g., Hall et al.,Adv. Cancer Res., 68, 67-108 (1996); Kamb, Trends in Genetics, 11,136-140 (1995); Kamb et al., Science, 264, 436-440 (1994).

[0012] A large number of small molecule ATP-site antagonists have beenidentified as CDK inhibitors. (See, Webster, Exp. Opin. Invest. Drugs,7, 865-887 (1998), Stover, Et al., Curr. Opin. Drug Disc. Dev., 2,274-285(1999), Gray et al., Curr. Med. Chem., 6, 859-875 (1999),Sielecki, et al., J. Med. Chem., 43, 1-18 (2000), Crews, et al., Curr.Opin. Chem. Biol., 4, 47-53 (2000), Buolamwini, Curr. Pharm. Des., 6,379-392 (2000), and Rosania, et al., Exp. Opin. Ther. Pat., 10, 215-230(2000)). Moreover, the use of compounds as anti-proliferativetherapeutic agents that inhibit CDKs is the subject of several patentsand publications. For example, U.S. Pat. No. 5,621,082 to Xiong et al.,discloses nucleic acid encoding an inhibitor of CDK6 and European PatentPublication No. 0 666 270 A2 describes peptides and peptidemimetics thatact as inhibitors of CDK1 and CDK2. WIPO International Publication No.WO 97/16447 discloses certain analogs of chromones that are inhibitorsof cyclin-dependent kinases, in particular of CDK/cyclin complexes suchas CDK4/cyclin D1, which may be used for inhibiting excessive orabnormal cell proliferation, and therefore for treating cancer. WIPOInternational Publication No. WO 99/21845 describes 4-aminothiazolederivatives that are useful as CDK inhibitors.

[0013] There is still a need, however, for small-molecule compounds thatmay be readily synthesized and are effective in inhibiting one or moreCDKs or CDK/cyclin complexes. Because CDK4 may serve as a generalactivator of cell division in most cells, and complexes of CDK4 andD-type cyclins govern the early G₁ phase of the cell-cycle, there is aneed for effective inhibitors of CDK4, and D-type cyclin complexesthereof, for treating one or more types of tumors. Also, the pivotalroles of cyclin E/CDK2 and cyclin B/CDK1 kinases in the G1/S phase andG2/M transitions, respectively offer additional targets for therapeuticintervention in suppressing deregulated cell-cycle progression incancer.

[0014] Another protein kinase, CHK-1, plays an important role as acheckpoint in cell-cycle progression. Checkpoints are control systemsthat coordinate cell-cycle progression by influencing the formation,activation and subsequent inactivation of the cyclin-dependent kinases.Checkpoints prevent cell-cycle progression at inappropriate times,maintain the metabolic balance of cells while the cell is arrested, andin some instances can induce apoptosis (programmed cell death) when therequirements of the checkpoint have not been met. See, e.g., O'Connor,Cancer Surveys, 29, 151-182 (1997); Nurse, Cell, 91, 865-867 (1997);Hartwell et al., Science, 266, 1821-1828 (1994); Hartwell et al.,Science, 246, 629-634 (1989).

[0015] One series of checkpoints monitors the integrity of the genomeand, upon sensing DNA damage, these “DNA damage checkpoints” blockcell-cycle progression in G₁ & G₂ phases, and slow progression through Sphase. O'Connor, Cancer Surveys, 29, 151-182 (1997); Hartwell et al.,Science, 266, 1821-1828 (1994). This action enables DNA repair processesto complete their tasks before replication of the genome and subsequentseparation of this genetic material into new daughter cells takes place.Importantly, the most commonly mutated gene in human cancer, the p53tumor suppressor gene, produces a DNA damage checkpoint protein thatblocks cell-cycle progression in G₁ phase and/or induces apoptosis(programmed cell death) following DNA damage. Hartwell et al., Science,266, 1821-1828 (1994). The p53 tumor suppressor has also been shown tostrengthen the action of a DNA damage checkpoint in G₂ phase of thecell-cycle. See, e.g., Bunz et al., Science, 28, 1497-1501 (1998);Winters et al., Oncogene, 17, 673-684 (1998); Thompson, Oncogene, 15,3025-3035 (1997).

[0016] Given the pivotal nature of the p53 tumor suppressor pathway inhuman cancer, therapeutic interventions that exploit vulnerabilities inp53-defective cancer have been actively sought. One emergingvulnerability lies in the operation of the G₂ checkpoint in p53defective cancer cells. Cancer cells, because they lack G₁ checkpointcontrol, are particularly vulnerable to abrogation of the last remainingbarrier protecting them from the cancer killing effects of DNA-damagingagents: the G₂ checkpoint. The G₂ checkpoint is regulated by a controlsystem that has been conserved from yeast to humans. Important in thisconserved system is a kinase, CHK-1, which transduces signals from theDNA-damage sensory complex to inhibit activation of the cyclin B/Cdc2kinase, which promotes mitotic entry. See, e.g., Peng et al., Science,277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997).Inactivation of CHK-1 has been shown to both abrogate G₂ arrest inducedby DNA damage inflicted by either anticancer agents or endogenous DNAdamage, as well as result in preferential killing of the resultingcheckpoint defective cells. See, e.g., Nurse, Cell, 91, 865-867 (1997);Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363,368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell, 5, 147-160(1994).

[0017] Selective manipulation of checkpoint control in cancer cellscould afford broad utilization in cancer chemotherapeutic andradiotherapy regimens and may, in addition, offer a common hallmark ofhuman cancer “genomic instability” to be exploited as the selectivebasis for the destruction of cancer cells. A number of factors placeCHK-1 as a pivotal target in DNA-damage checkpoint control. Theelucidation of inhibitors of this and functionally related kinases suchas Cds1/CHK-2, a kinase recently discovered to cooperate with CHK-1 inregulating S phase progression (see Zeng et al., Nature, 395, 507-510(1998); Matsuoka, Science, 282, 1893-1897 (1998)), could providevaluable new therapeutic entities for the treatment of cancer.

[0018] Tyrosine kinases can be of the receptor type (havingextracellular, transmembrane and intracellular domains) or thenon-receptor type (being wholly intracellular). At least one of thenon-receptor protein tyrosine kinases, namely, LCK, is believed tomediate the transduction in T-cells of a signal from the interaction ofa cell-surface protein (Cd4) with a cross-linked anti-Cd4 antibody. Amore detailed discussion of non-receptor tyrosine kinases is provided inBolen, Oncogene, 8, 2025-2031 (1993), which is incorporated herein byreference.

[0019] In addition to the protein kinases identified above, many otherprotein kinases have been considered to be therapeutic targets, andnumerous publications disclose inhibitors of kinase activity, asreviewed in the following: McMahon et al., Current Opinion in DrugDiscovery & Development, 1, 131-146 (1998); Strawn et al., Exp. Opin.Invest. Drugs, 7, 553-573 (1998); Adams et al., Curr. Opin. Drug Disc.Dev., 2, 96-109 (1999), Stover et al., Curr. Opin. Drug Disc. Dev., 2,274-285 (1999), Toledo et al., Curr. Med. Chem., 6, 775-805 (1999), andGarcía-Echeverría, et al., Med. Res. Rev., 20, 28-57 (2000).

[0020] There is still a need, however, for effective inhibitors ofprotein kinases. Moreover, as is well understood by those skilled in theart, it is desirable for kinase inhibitors to possess both high affinityfor the target kinase as well as high selectivity versus other proteinkinases.

SUMMARY OF THE INVENTION

[0021] Thus, an objective of the invention is to provide potentinhibitors of protein kinases. Another objective of the invention is toprovide effective kinase inhibitors having a strong and selectiveaffinity for a particular kinase.

[0022] These and other objectives of the invention, which will becomeapparent from the following description, have been achieved by thediscovery of amide compounds, pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts thereof (such compounds, prodrugs, metabolites and salts arecollectively referred to as “agents”) described below, which modulateand/or inhibit the activity of protein kinases.

[0023] Pharmaceutical compositions containing such agents are useful intreating various diseases and disorders associated with uncontrolled orunwanted angiogenesis and/or cellular proliferation, such as cancer,autoimmune diseases, viral diseases, fungal diseases, neurodegenerativedisorders and cardiovascular diseases. Thus, pharmaceutical compositionscontaining such agents are useful in the treatment of diabeticretinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis.

[0024] Further, the agents have advantageous properties relating tomodulation and/or inhibition of the kinase activity associated withVEGF-R, FGF-R, CDK complexes (e.g., CDK1, CDK2, CDK4 and CDK6), CHK-1,TEK, and LCK. Thus, pharmaceutical compositions containing such agentsare useful in the treatment of diseases and disorders mediated by kinaseactivity, such as cancer.

[0025] In a general aspect, the invention relates to compoundsrepresented by the Formula I:

[0026] wherein:

[0027] R¹ is a moiety of the formula

[0028] where

[0029] Z is CH or NH, and Q is a moiety such that R¹ is a substituted orunsubstituted monocyclic or bicyclic heteroaryl which has at least twocarbon atoms in the heteroaryl ring system;

[0030] X is selected from CH₂, O, S, and NH;

[0031] Y is selected from CH₂, O, and S, provided that at least one of Xand Y is CH₂, or X and Y together with the bond there-between form acyclopropyl;

[0032] R² and R³ are independently selected from hydrogen, methyl,halogen, trifluoromethyl, and cyano; and

[0033] R⁴ is

[0034] where R⁵ is a substituted or unsubstituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, O—R⁷, NR⁸R⁹, C₁-C₈ alkyl, or monocyclicheterocycloalkyl group, R⁶ is a substituted or unsubstituted aryl,heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, O—R⁷, C(O)R⁷, NR⁸R⁹,C₂-C₈ alkyl, or monocyclic heterocycloalkyl group, where R⁷ is asubstituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl, R⁸ is hydrogen or a substituted or unsubstituted alkyl,and R⁹ is a substituted or unsubstituted alkyl, aryl, heteroaryl,cycloalkyl, or heterocycloalkyl.

[0035] The invention is also directed to pharmaceutically acceptableprodrugs, pharmaceutically active metabolites, and pharmaceuticallyacceptable salts of the compounds of Formula I. Pharmaceuticallyacceptable salts of such active metabolites are also provided.Advantageous methods of making the compounds of the Formula I are alsodescribed.

[0036] In a preferred general embodiment, the invention relates tocompounds of the Formula I wherein R¹ is a substituted or unsubstitutedheteroaryl group selected from:

[0037] where

[0038] X is selected from CH₂, O, and S;

[0039] Y is selected from CH₂ and S, provided that at least one of X andY is CH₂;

[0040] R² and R³ are independently selected from hydrogen, methyl,fluorine, and chlorine; and

[0041] R⁴ is

[0042] where R⁵ is a substituted or unsubstituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, O—R⁷, NR⁸R⁹, C₁-C₈ alkyl, or monocyclicheterocycloalkyl group, R⁶ is a substituted or unsubstituted aryl,heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, O—R⁷, C(O)R⁷, NR⁸R⁹,C₂-C₈ alkyl, or monocyclic heterocycloalkyl group, where R⁷ is asubstituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl, R⁸ is hydrogen or a substituted or unsubstituted alkyl,and R⁹ is a substituted or unsubstituted alkyl, aryl, heteroaryl,cycloalkyl, or heterocycloalkyl.

[0043] Especially preferred are compounds represented by the Formula II:

[0044] wherein:

[0045] X is selected from CH₂, O, and S;

[0046] Y is selected from CH₂ and S, provided that at least one of X andY is CH₂;

[0047] R² and R³ are independently selected from hydrogen, methyl,fluorine, and chlorine;

[0048] R⁴ is

[0049] where R⁵ and R⁶ are each independently a substituted orunsubstituted aryl or heteroaryl; and R¹⁰ is a substituted orunsubstituted alkenyl, aryl, heteroaryl, or NHR⁹, where R⁹ is asubstituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl.

[0050] In another embodiment, the present invention is directed tocompounds represented by the Formula III:

[0051] wherein:

[0052] X is selected from CH₂, O, S, and NH;

[0053] Y is selected from CH₂, O, and S, provided that at least one of Xand Y is CH₂, or X and Y together with the bond there-between form acyclopropyl;

[0054] R² and R³ are independently selected from hydrogen, methyl,halogen, trifluoromethyl, and cyano; and

[0055] R⁴ is

[0056] where R⁵ is a substituted or unsubstituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, O—R⁷, NR⁸R⁹, C₁-C₈ alkyl, or monocyclicheterocycloalkyl group, R⁶ is a substituted or unsubstituted aryl,heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, O—R⁷, C(O)R⁷, NR⁸R⁹,C₂-C₈ alkyl, or monocyclic heterocycloalkyl group, where R⁷ is asubstituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl, R⁸ is hydrogen or a substituted or unsubstituted alkyl,and R⁹ is a substituted or unsubstituted alkyl, aryl, heteroaryl,cycloalkyl, or heterocycloalkyl; and pharmaceutically acceptable saltsthereof and pharmaceutically acceptable prodrugs thereof.

[0057] In preferred embodiments of compounds of Formula III:

[0058] X is selected from CH₂, O, and S;

[0059] Y is selected from CH₂ and S, provided that at least one of X andY is CH₂;

[0060] R² and R³ are independently selected from hydrogen, methyl,fluorine, and chlorine; and

[0061] R⁴ is

[0062] where R⁵ and R⁶ are each independently a substituted orunsubstituted aryl or heteroaryl.

[0063] Especially preferred are compounds represented by the FormulaIII, wherein:

[0064] X is CH₂;

[0065] Y is S;

[0066] R² and R³ are independently selected from hydrogen, methyl,fluorine, and chlorine; and

[0067] R⁴ is

[0068] where R⁵ and R⁶ are each independently a substituted orunsubstituted aryl or heteroaryl.

[0069] The invention also relates to a method of modulating and/orinhibiting the kinase activity of VEGF-R, FGF-R, a CDK complex, CHK-1,TEK, and/or LCK by administering a compound of the Formula I, II, orIII, or a pharmaceutically acceptable prodrug, pharmaceutically activemetabolites, or pharmaceutically acceptable salt thereof. Preferably,compounds of the present invention have selective kinase activity—i.e.,they possess significant activity against one specific kinase whilepossessing less or minimal activity against a different kinase. In onepreferred embodiment of the invention, compounds of the presentinvention are those of Formula I, II, or III, possessing substantiallyhigher potency against VEGF receptor tyrosine kinase than against LCKreceptor tyrosine kinase. The invention is also directed to methods ofmodulating VEGF receptor tyrosine kinase activity without significantlymodulating LCK receptor tyrosine kinase activity.

[0070] The invention also relates to pharmaceutical compositions eachcomprising: an effective amount of an agent selected from compounds ofthe Formula I, II, and III, and pharmaceutically acceptable salts,pharmaceutically active metabolites, and pharmaceutically acceptableprodrugs thereof; and a pharmaceutically acceptable carrier or vehiclefor such agent.

[0071] The invention further provides methods of treating cancer as wellas other disease states associated with unwanted angiogenesis and/orcellular proliferation, comprising administering effective amounts ofsuch agents to a patient in need of such treatment.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

[0072] The inventive compounds of the Formula I, II, and III are usefulfor mediating the activity of protein kinases. More particularly, thecompounds are useful as anti-angiogenesis agents and as agents formodulating and/or inhibiting the activity of protein kinases, thusproviding treatments for cancer or other diseases associated withcellular proliferation mediated by protein kinases.

[0073] The term “alkyl” as used herein refers to straight- andbranched-chain alkyl groups having one to twelve carbon atoms. Exemplaryalkyl groups include methyl (Me), ethyl, n-propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl,hexyl, isohexyl, and the like. The term “alkenyl” refers to straight-and branched-chain alkenyl groups having from two to twelve carbonatoms. Illustrative alkenyl groups include prop-2-enyl, but-2-enyl,but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, and the like.

[0074] The term “cycloalkyl” refers to saturated or unsaturatedcarbocycles having from three to twelve carbon atoms, including bicyclicand tricyclic cycloalkyl structures. Suitable cycloalkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and thelike.

[0075] A “heterocycloalkyl” group is intended to mean a saturated orunsaturated monocyclic radical containing carbon atoms, preferably 4 or5 ring carbon atoms, and at least one heteroatom selected from nitrogen,oxygen and sulfur.

[0076] The terms “aryl” (Ar) and “heteroaryl” refer to monocyclic andpolycyclic unsaturated or aromatic ring structures, with “aryl”referring to those that are carbocycles and “heteroaryl” referring tothose that are heterocycles. Examples of aromatic ring structuresinclude phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl,pyrrolyl, pyridyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl,pyridazinyl, 1,2,3-triazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1-H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl(thianaphthenyl), and the like. Such moieties may be optionallysubstituted by one or more suitable substituents, for example, asubstituent selected from a halogen (F, Cl, Br or I); lower alkyl; OH;NO₂; CN; CO₂H; O-lower alkyl; aryl; aryl-lower alkyl; CO₂CH₃; CONH₂;OCH₂CONH₂; NH₂; SO₂NH₂; OCHF₂; CF₃; OCF₃; and the like. Such moietiesmay also be optionally substituted by a fused-ring structure or bridge,for example OCH₂—O.

[0077] The term “alkoxy” is intended to mean the radical —O-alkyl.Illustrative examples include methoxy, ethoxy, propoxy, and the like.

[0078] The term “halogen” represents chlorine, fluorine, bromine oriodine. The term “halo” represents chloro, fluoro, bromo or iodo.

[0079] In general, the various moieties or functional groups forvariables in the formulae may be optionally substituted by one or moresuitable substituents. Exemplary substituents include a halogen (F, Cl,Br, or I), lower alkyl, —OH, —NO₂, —CN, —CO₂H, —O-lower alkyl, -aryl,-aryl-lower alkyl, —CO₂CH₃, —CONH₂, —OCH₂CONH₂, —NH₂, —SO₂NH₂, haloalkyl(e.g., —CF₃, —CH₂CF₃), —O-haloalkyl (e.g., —OCF₃, —OCHF₂), and the like.

[0080] It is understood that compounds of Formula I, II, and III mayexhibit the phenomenon of tautomerism and that the formula drawingswithin this specification can represent only one of the possibletautomeric forms. It is to be understood that the invention encompassesany tautomeric form which modulates and/or inhibits kinase activity andis not to be limited merely to any one tautomeric form utilized withinthe formula drawings.

[0081] Some of the inventive compounds may exist as single stereoisomers(i.e., essentially free of other stereoisomers), racemates, and/ormixtures of enantiomers and/or diastereomers. All such singlestereoisomers, racemates and mixtures thereof are intended to be withinthe scope of the present invention. Preferably, the inventive compoundsthat are optically active are used in optically pure form.

[0082] As generally understood by those skilled in the art, an opticallypure compound having one chiral center (i.e., one asymmetric carbonatom) is one that consists essentially of one of the two possibleenantiomers (i.e., is enantiomerically pure), and an optically purecompound having more than one chiral center is one that is bothdiastereomerically pure and enantiomerically pure. Preferably, thecompounds of the present invention are used in a form that is at least90% optically pure, that is, a form that contains at least 90% of asingle isomer (80% enantiomeric excess (“e.e.”) or diastereomeric excess(“d.e.”)), more preferably at least 95% (90% e.e. or d.e.), even morepreferably at least 97.5% (95% e.e. or d.e.), and most preferably atleast 99% (98% e.e. or d.e.).

[0083] Additionally, the formulas are intended to cover solvated as wellas unsolvated forms of the identified structures. For example, Formula Iincludes compounds of the indicated structure in both hydrated andnon-hydrated forms. Other examples of solvates include the structures incombination with isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid, or ethanolamine.

[0084] In addition to compounds of the Formula I, II, and III, theinvention includes pharmaceutically acceptable prodrugs,pharmaceutically active metabolites, and pharmaceutically acceptablesalts of such compounds. Pharmaceutically active salts of such activemetabolites are also included.

[0085] The term “pharmaceutically acceptable” means pharmacologicallyacceptable and substantially non-toxic to the subject being administeredthe cell-cycle control agent.

[0086] “A pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound.

[0087] “A pharmaceutically active metabolite” is intended to mean apharmacologically active product produced through metabolism in the bodyof a specified compound or salt thereof. Metabolites of a compound maybe identified using routine techniques known in the art and theiractivities determined using tests such as those described herein.

[0088] Prodrugs and active metabolites of a compound may be identifiedusing routine techniques known in the art. See, e.g., Bertolini et al.,J. Med. Chem., 40, 2011-2016 (1997); Shan, et al., J. Pharm. Sci., 86(7), 765-767; Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor,Advances in Drug Res., 13, 224-331 (1984); Bundgaard, Design of Prodrugs(Elsevier Press 1985); and Larsen, Design and Application of Prodrugs,Drug Design and Development (Krogsgaard-Larsen et al., eds., HarwoodAcademic Publishers, 1991).

[0089] “A pharmaceutically acceptable salt” is intended to mean a saltthat retains the biological effectiveness of the free acids and bases ofthe specified compound and that is not biologically or otherwiseundesirable. A compound of the invention may possess a sufficientlyacidic, a sufficiently basic, or both functional groups, and accordinglyreact with any of a number of inorganic or organic bases, and inorganicand organic acids, to form a pharmaceutically acceptable salt. Exemplarypharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such as salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

[0090] If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonicacid, pyrovic acid, oxalic acid, glycolic acid, salicylic acid, apyranosidyl acid, such as glucuronic acid or galacturonic acid, analpha-hydrozy acid, such as citric acid or tartaric acid, an amino acid,such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid or cinnamic acid, a sulfonic acid, such asp-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0091] If the inventive compound is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include organic salts derived from aminoacids, such as glycine and arginine, ammonia, primary, secondary, andtertiary amines, and cyclic amines, such as piperidine, morpholine andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0092] In the case of agents that are solids, it is understood by thoseskilled in the art that the inventive compounds and salts may exist indifferent crystal or polymorphic forms, all of which are intended to bewithin the scope of the present invention and specified formulas.

[0093] Therapeutically effective amounts of the agents of the inventionmay be used to treat diseases mediated by modulation or regulation ofprotein kinases. An “effective amount” is intended to mean that amountof an agent that, when administered to a mammal in need of suchtreatment, is sufficient to effect treatment for a disease mediated bythe activity of one or more protein kinases, such as tyrosine kinases.Thus, e.g., a therapeutically effective amount of a compound of theFormula I, salt, active metabolite or prodrug thereof is a quantitysufficient to modulate, regulate, or inhibit the activity of one or moreprotein kinases such that a disease condition which is mediated by thatactivity is reduced or alleviated.

[0094] The amount of a given agent that will correspond to such anamount will vary depending upon factors such as the particular compound,disease condition and its severity, the identity (e.g., weight) of themammal in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art. “Treating” is intended to mean atleast the mitigation of a disease condition in a mammal, such as ahuman, that is affected, at least in part, by the activity of one ormore protein kinases, such as tyrosine kinases, and includes: preventingthe disease condition from occurring in a mammal, particularly when themammal is found to be predisposed to having the disease condition buthas not yet been diagnosed as having it; modulating and/or inhibitingthe disease condition; and/or alleviating the disease condition.

[0095] The inventive agents may be prepared using the reaction routesand synthesis schemes as described below, employing the techniquesavailable in the art using starting materials that are readilyavailable.

[0096] Compounds of formula I where R⁴ is CONHR⁵ may be prepared asshown in Scheme 1.

[0097] As shown in Scheme 1, carboxylic acids of formula IV are coupledto amines of formula V to give compounds of formula I (R⁴═CONHR⁵). Thecoupling may be carried out employing various peptide coupling reagents,for example 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide HCl (EDC),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), orbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(pyBop), in polar aprotic solvents, such as N, N-dimethylforamide (DMF)or dichloromethane. Alternatively, the acid IV may be first converted toan acid chloride by treatment with, for example, oxalyl chloride orthionyl chloride, and then, without purification, reacted with amines offormula V to give compounds of formula I (R⁴═CONHR⁵).

[0098] Compounds of formula I where R⁴ is NHCOR⁶ may be prepared asshown in Scheme 2.

[0099] Carboxylic acids of formula VII are coupled to amines of formulaVI to give compounds of formula I (R⁴═NHCOR⁶). The coupling may becarried out employing with various peptide coupling reagents, forexample EDC, HATU, or pyBOP, in polar aprotic solvents, such as DMF ordichloromethane. Alternatively, the acid VII may be first converted toan acid chloride by treatment with, for example, oxalyl chloride orthionyl chloride, and then, without purification, reacted with amines offormula VI to give compounds of formula I (R⁴═NHCOR⁶).

[0100] Compounds of formula I-a may be prepared by the reaction shown inScheme 3.

[0101] Compounds of formula IX (R═R⁴) are treated with compounds offormula VIII, where Lg is a suitable leaving group such as chloride,bromide, or mesylate, in a dipolar aprotic solvent such as acetone, DMF,or DMSO, in the presence of a suitable base, such as potassiumcarbonate, cesium carbonate, sodium hydride, and the like, to provide,after extractive workup and conventional purification, compounds offormula I-a. Alternatively, this reaction may be carried out in the samemanner with compounds of formula XI (R═CO₂R¹¹, where R¹¹ is hydrogen ora suitable carboxylic acid protecting group, such as methyl, ethyl, orbenzyl) to give compounds of formula IV-a. In addition, the reactioncarried out with compounds of formula IX (R═NH₂) provides compounds offormula VI-a.

[0102] Compounds of formula I-b may be prepared by the reaction shown inScheme 4.

[0103] Compounds of formula XI (R═R⁴), where Lg is a suitable leavinggroup such as chloride, bromide, or mesylate, are treated with compoundsof formula X in a dipolar aprotic solvent such as acetone, DMF, or DMSO,in the presence of a suitable base, such as potassium carbonate, cesiumcarbonate, sodium hydride, and the like, to provide, after extractiveworkup and conventional purification, compounds of formula I-b.Alternatively, this reaction may be carried out in the same manner withcompounds of formula XI (R═CO₂R¹¹, where R¹¹ is hydrogen or a suitablecarboxylic acid protecting group, such as methyl, ethyl, or benzyl) togive compounds of formula IV-b. In addition, the reaction carried outwith compounds of formula XI (R═NH₂) provides compounds of formula VI-b.

[0104] Compounds of formula I-c may be prepared by the reaction shown inScheme 5.

[0105] Compounds of formula XII, where W is a suitable group that canparticipate in a palladium-catalyzed coupling reaction such as bromide,iodide, or triflate, are allowed to react with acetylenes of formulaXIII in the presence of a suitable palladium catalyst, such asdichlorobis(triphenylphosphine)palladium, and a copper catalyst, such ascuprous iodide, in the presence of a suitable base, such as piperidine,triethylaamine or diisopropylethylamine, in an aprotic solvent, such asTHF or DMF, at a temperature between 25° C. and 125° C., for 1 to 24hours. After extractive work-up and conventional purification, removalof the silyl protecting group is effected with, for example, eithertetrabutylammonium fluoride in THF or sodium hydroxide in methanol, toprovide compounds of formula XIV.

[0106] Under similar catalyzed coupling conditions as those describedabove, compounds of formula XV can be reacted with those of formula XIVto yield compounds of formula XVI. Catalytic hydrogenation of alkynes offormula XVI provides compounds of formula I-c after filtration andconvention purification. Typical catalytic conditions include catalystssuch as palladium, rhodium, preferably palladium-on-carbon, in asuitable solvent such as C₁-C₄ alcohols, preferably ethanol.

[0107] Compounds of formula II-a may be prepared as shown in Scheme 6.

[0108] Thioamides of formula XVII are treated with two molar equivalentsof a suitable strong base, such as n-butyllithium or lithiumdiisopropylamide, in a suitable solvent, such as THF, at −78° C. to 0°C., to give a solution of thioamide dianion, which is further treatedwith less than or equal to 0.5 molar equivalents of compounds of formulaXVIII. Conventional aqueous work-up and purification then providescompounds of formula XIX, which upon treatment with hydrazine,preferably in the presence of acetic acid, in ethanol at 0° C. to 50°C., preferably at room temperature, provides compounds of formula II-a.

[0109] Compounds of formula II-b may be prepared as shown in Scheme 7.

[0110] Ketones of formula XX, where R¹² is substituted or unsubstitutedalkenyl, aryl, or heteroaryl, are converted to hydrazones of formula XXIby treatment with t-butyl carbazate and acetic acid in ethanol.Treatment of hydrazones of formula XXI with two molar equivalents of asuitable strong base, such as n-butyllithium or lithiumdiisopropylamide, in a suitable solvent, such as THF, at −78° C. to 0°C., generates a solution of hydrazone dianion, which is further treatedwith less than or equal to 0.5 molar equivalents of compounds of formulaXVIII. Conventional aqueous work-up and purification then providescompounds of formula XXII, which upon further treatment with a suitableacid, such as trifluoroacetic acid, provides compounds of formula II-b.

[0111] Compounds of formula XVIII are prepared as shown in Scheme 8.

[0112] Thus, compounds of formula XVIII-a and XVIII-b are prepared byalkylation of compounds of formula IX with N-methoxy-N-methylchloroacetamide in a like manner to that shown in Scheme 3 above.Compounds of formula XVIII-c may be prepared by (1) reaction ofaldehydes of formula XXIII with the anion derived fromN-methoxy-N-methyl triethylphosphonoacetamide to give unsaturated amidesof formula XXIV, and (2) reduction of compounds of formula XXIV with,for example, hydrogen in the presence of palladium on carbon to providecompounds of formula XVIII-c.

[0113] Other compounds of Formula I, II, and III may be prepared inmanners analogous to the general procedures described above or thedetailed procedures described in the examples herein.

[0114] The affinity of the compounds of the invention for a receptor maybe enhanced by providing multiple copies of the ligand in closeproximity, preferably using a scaffolding provided by a carrier moiety.It has been shown that provision of such multiple valence compounds withoptimal spacing between the moieties dramatically improves binding to areceptor. See e.g., Lee et al., Biochem, 23, 4255 (1984). Themultivalency and spacing can be controlled by selection of a suitablecarrier moiety or linker units. Such moieties include molecular supportswhich contain a multiplicity of functional groups that can be reactedwith functional groups associated with the compounds of the invention.Of course, a variety of carriers can be used, including proteins such asBSA or HAS, a multiplicity of peptides including, for example,pentapeptides, decapeptides, pentadecapeptides, and the like. Thepeptides or proteins can contain the desired number of amino acidresidues having free amino groups in their side chains; however, otherfunctional groups, such as mercapto (—SH) groups or hydroxyl (—OH)groups, can also be used to obtain stable linkages.

[0115] Compounds that potently regulate, modulate, or inhibit theprotein kinase activity associated with receptors VEGF, FGF, CDKcomplexes, TEK, CHK-1, and LCK, among others, and which inhibitangiogenesis and/or cellular profileration is desirable and is onepreferred embodiment of the present invention. The present invention isfurther directed to methods of modulating or inhibiting protein kinaseactivity, for example in mammalian tissue, by administering an inventiveagent. The activity of the inventive compounds as modulators of proteinkinase activity, such as the activity of kinases, may be measured by anyof the methods available to those skilled in the art, including in vivoand/or in vitro assays. Examples of suitable assays for activitymeasurements include those described in Parast C. et al., BioChemistry,37, 16788-16801 (1998); Jeffrey et al., Nature, 376, 313-320 (1995);WIPO International Publication No. WO 97/34876; and WIPO InternationalPublication No. WO 96/14843. These properties may be assessed, forexample, by using one or more of the biological testing procedures setout in the examples below.

[0116] The active agents of the invention may be formulated intopharmaceutical compositions as described below. Pharmaceuticalcompositions of this invention comprise an effective modulating,regulating, or inhibiting amount of a compound of Formula I, II, or IIIand an inert, pharmaceutically acceptable carrier or diluent. In oneembodiment of the pharmaceutical compositions, efficacious levels of theinventive agents are provided so as to provide therapeutic benefitsinvolving modulation of protein kinases. By “efficacious levels” ismeant levels in which the effects of protein kinases are, at a minimum,regulated. These compositions are prepared in unit-dosage formappropriate for the mode of administration, e.g., parenteral or oraladministration.

[0117] An inventive agent is administered in conventional dosage formprepared by combining a therapeutically effective amount of an agent(e.g., a compound of Formula I) as an active ingredient with appropriatepharmaceutical carriers or diluents according to conventionalprocedures. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation.

[0118] The pharmaceutical carrier employed may be either a solid orliquid. Exemplary of solid carriers are lactose, sucrose, talc, gelatin,agar, pectin, acacia, magnesium stearate, stearic acid and the like.Exemplary of liquid carriers are syrup, peanut oil, olive oil, water andthe like. Similarly, the carrier or diluent may include time-delay ortime-release material known in the art, such as glyceryl monostearate orglyceryl distearate alone or with a wax, ethylcellulose,hydroxypropylmethylcellulose, methylmethacrylate and the like.

[0119] A variety of pharmaceutical forms can be employed. Thus, if asolid carrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier may vary, but generally will befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation will be in the form of syrup, emulsion, soft gelatincapsule, sterile injectable solution or suspension in an ampule or vialor non-aqueous liquid suspension.

[0120] To obtain a stable water-soluble dose form, a pharmaceuticallyacceptable salt of an inventive agent is dissolved in an aqueoussolution of an organic or inorganic acid, such as 0.3M solution ofsuccinic acid or citric acid. If a soluble salt form is not available,the agent may be dissolved in a suitable cosolvent or combinations ofcosolvents. Examples of suitable cosolvents include, but are not limitedto, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80,gylcerin and the like in concentrations ranging from 0-60% of the totalvolume. In an exemplary embodiment, a compound of Formula I is dissolvedin DMSO and diluted with water. The composition may also be in the formof a solution of a salt form of the active ingredient in an appropriateaqueous vehicle such as water or isotonic saline or dextrose solution.

[0121] It will be appreciated that the actual dosages of the agents usedin the compositions of this invention will vary according to theparticular complex being used, the particular composition formulated,the mode of administration and the particular site, host and diseasebeing treated. Optimal dosages for a given set of conditions can beascertained by those skilled in the art using conventionaldosage-determination tests in view of the experimental data for anagent. For oral administration, an exemplary daily dose generallyemployed is from about 0.001 to about 1000 mg/kg of body weight, morepreferably from about 0.001 to about 50 mg/kg body weight, with coursesof treatment repeated at appropriate intervals. Administration ofprodrugs are typically dosed at weight levels which are chemicallyequivalent to the weight levels of the fully active form.

[0122] The compositions of the invention may be manufactured in mannersgenerally known for preparing pharmaceutical compositions, e.g., usingconventional techniques such as mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orlyophilizing. Pharmaceutical compositions may be formulated in aconventional manner using one or more physiologically acceptablecarriers, which may be selected from excipients and auxiliaries thatfacilitate processing of the active compounds into preparations whichcan be used pharmaceutically.

[0123] Proper formulation is dependent upon the route of administrationchosen. For injection, the agents of the invention may be formulatedinto aqueous solutions, preferably in physiologically compatible bufferssuch as Hanks's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art.

[0124] For oral administration, the compounds can be formulated readilyby combining the active compounds with pharmaceutically acceptablecarriers known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained using a solid excipient in admixture with theactive ingredient (agent), optionally grinding the resulting mixture,and processing the mixture of granules after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients include: fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; and cellulose preparations, for example, maizestarch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose,or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

[0125] Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used, which may optionallycontain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

[0126] Pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillerssuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate, and, optionally, stabilizers. In softcapsules, the active agents may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration. For buccal administration, the compositions may take theform of tablets or lozenges formulated in conventional manner.

[0127] For administration intranasally or by inhalation, the compoundsfor use according to the present invention are conveniently delivered inthe form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator and the like may beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

[0128] The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit-dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

[0129] Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active agents may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

[0130] For administration to the eye, a compound of the formula I, II,or m is delivered in a pharmaceutically acceptable ophthalmic vehiclesuch that the compound is maintained in contact with the ocular surfacefor a sufficient time period to allow the compound to penetrate thecorneal and internal regions of the eye, including, for example, theanterior chamber, posterior chamber, vitreous body, aqueous humor,vitreous humor, cornea, iris/cilary, lens, choroid/retina and selera.The pharmaceutically acceptable ophthalmic vehicle may be an ointment,vegetable oil, or an encapsulating material. A compound of the inventionmay also be injected directly into the vitreous and aqueous humor.

[0131] Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use. The compounds may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g, containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0132] In addition to the formulations described above, the compoundsmay also be formulated as a depot preparation. Such long-actingformulations may be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion-exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

[0133] A pharmaceutical carrier for hydrophobic compounds is a cosolventsystem comprising benzyl alcohol, a nonpolar surfactant, awater-miscible organic polymer, and an aqueous phase. The cosolventsystem may be a VPD co-solvent system. VPD is a solution of 3% w/vbenzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.The VPD co-solvent system (VPD:5W) contains VPD diluted 1:1 with a 5%dextrose in water solution. This co-solvent system dissolves hydrophobiccompounds well, and itself produces low toxicity upon systemicadministration. Naturally, the proportions of a co-solvent system may bevaried considerably without destroying its solubility and toxicitycharacteristics. Furthermore, the identity of the co-solvent componentsmay be varied: for example, other low-toxicity nonpolar surfactants maybe used instead of polysorbate 80; the fraction size of polyethyleneglycol may be varied; other biocompatible polymers may replacepolyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars orpolysaccharides may be substituted for dextrose.

[0134] Alternatively, other delivery systems for hydrophobicpharmaceutical compounds may be employed. Liposomes and emulsions areknown examples of delivery vehicles or carriers for hydrophobic drugs.Certain organic solvents such as dimethylsulfoxide also may be employed,although usually at the cost of greater toxicity. Additionally, thecompounds may be delivered using a sustained-release system, such assemipermeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are known by those skilled in the art. Sustained-releasecapsules may, depending on their chemical nature, release the compoundsfor a few weeks up to over 100 days. Depending on the chemical natureand the biological stability of the therapeutic reagent, additionalstrategies for protein stabilization may be employed.

[0135] The pharmaceutical compositions also may comprise suitable solid-or gel-phase carriers or excipients. Examples of such carriers orexcipients include calcium carbonate, calcium phosphate, sugars,starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols.

[0136] Some of the compounds of the invention may be provided as saltswith pharmaceutically compatible counter ions. Pharmaceuticallycompatible salts may be formed with many acids, including hydrochloric,sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend tobe more soluble in aqueous or other protonic solvents than are thecorresponding free-base forms.

[0137] The preparation of preferred compounds of the present inventionis described in detail in the following examples, but the artisan willrecognize that the chemical reactions described may be readily adaptedto prepare a number of other protein kinase inhibitors of the invention.For example, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by changing to other suitable reagents known in the art, or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

EXAMPLES

[0138] In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius and all parts andpercentages are by weight. Reagents were purchased from commercialsuppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd.and were used without further purification unless otherwise indicated.Tetrahydrofuran (THF) and N,N-dimethylforamide (DMF) were purchased fromAldrich in Sure seal bottles and used as received. All solvents werepurified using standard methods readily known to those skilled in theart, unless otherwise indicated.

[0139] The reactions set forth below were done generally under apositive pressure of argon or nitrogen or with a drying tube, at ambienttemperature (unless otherwise stated), in anhydrous solvents, and thereaction flasks were fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. Analytical thin layer chromatography (TLC) was performed onglass-backed silica gel 60 F 254 plates and eluted with the appropriatesolvent ratios (v/v), and are denoted where appropriate. The reactionswere assayed by TLC and terminated as judged by the consumption ofstarting material.

[0140] Visualization of the TLC plates was generally done by ultravioletvisualization. Work-ups were typically done by doubling the reactionvolume with the reaction solvent or extraction solvent and then washingwith the indicated aqueous solutions using 25% by volume of theextraction volume unless otherwise indicated. Product solutions weredried over anhydrous Na₂SO₄ prior to filtration and evaporation of thesolvents under reduced pressure on a rotary evaporator and noted assolvents removed in vacuo. Products were purified by employing radialchromatography or flash column chromatography (Still et al., J. Org.Chem., 43, 2923 (1978)), the latter using Merck grade flash silica gel(47-61 μm) and a silica gel: crude material ratio of about 20:1 to 100:1unless otherwise stated. Hydrogenolysis was done at the pressureindicated in the examples or at ambient pressure.

[0141]¹H-NMR spectra were recorded on an instrument operating at 300 or500 MHz, and ¹³C-NMR spectra were recorded operating at 75 MHz. NMRspectra were obtained as CDCl₃ solutions (reported in ppm), usingchloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD₃OD(3.4 and 4.8 ppm and 49.3 ppm), or internally tetramethylsilane (0.00ppm) when appropriate. Other NMR solvents were used as needed. When peakmultiplicities are reported, the following abbreviations are used: s(singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br(broadened), dd (doublet of doublets), dt (doublet of triplets).Coupling constants, when given, are reported in Hertz (Hz).

[0142] Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IRSpectrometer as neat oils, as KBr pellets, or as CDCl₃ solutions, andwhen given are reported in wave numbers (cm⁻¹). All melting points (mp)are uncorrected.

[0143] Unless otherwise stated, the HPLC conditions are the following:Hewlett Packard ODS Hypersil (5 μm, 125×4 mm), 10% acetonitrile/0.1 Mammonium acetate from 0-2 minutes to 90% acetonitrile/0.1 M ammoniumacetate at 22 minutes, 1.0 mL/minute, detection at 254 nm.

[0144] Abbreviations for reagents, equipment, and techniques are definedas follows: MTBE (methyl t-butyl ether); DMSO (dimethylsulfoxide); DIEA(diisopropylethylamine); TEA (triethylamine); AcOH (acetic acid); DMAP(4-(dimethylamino)pyridine); EDC(1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide HCl); HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate); HOBt (N-hydroxybenzotriazole); PyBop(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate); MS (ESI) (Electrospray ionization massspectrometry); MS (FAB) (fast atom bombardment mass spectrometry); HRMS(FAB) (high resolution fast atom bombardment mass spectrometry); HRMS(MALDI) (high resolution matrix-assisted laser desorption/ionizationmass spectrometry); and APCIMS (atmospheric pressure chemical ionizationmass spectrometry).

EXAMPLE A-1N-(3,4,5-Trimethoxyphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide

[0145]

[0146] (a) To a solution of 3,4,5-trimethoxyaniline (3.0 g, 16.4 mmol)and triethylamine (2.5 mL, 18 mmol) in 100 mL dichloromethane at roomtemperature was added, via pipette, 3-(chloro-methyl)benzoyl chloride(2.4 mL, 16.9 mmol). After stirring at room temperature for 4 h, themixture was partitioned between chloroform (100 mL) and water (200 mL).The aqueous layer was extracted twice with chloroform (100 mL) and thecombined organics were washed with brine (100 mL), dried over Na₂SO₄,and concentrated to dryness. The crude residue was triturated with MTBEto obtain 5.22 g (95%) ofN-(3,4,5-trimethoxyphenyl)-3-(chloromethyl)benzamide, A-1a, as anoff-white solid which was collected by filtration: mp 138-145° C.; ¹HNMR (DMSO-d₆) δ 7.98 (s, 1H), 7.89 (d, 1H, J=7.8 Hz), 7.63 (d, 1H, J=7.8Hz), 7.52 (t, 1H, J=7.7 Hz), 7.20 (s, 2H), 4.83 (s, 2H), 3.75 (s, 6H),3.62 (s, 3H). Anal. calc'd for C₁₇H₁₈NO₄Cl.0.2H₂O: C, 60.16; H, 5.47; N,4.13; Cl, 10.45. Found: C, 60.18; H, 5.38; N, 4.17; Cl, 10.68.

[0147] (b) To a solution of 0.112 g (1 mmol) of 2-pyrazinethiol (Specs)and N-(3,4,5-trimethoxyphenyl)-3-(chloromethyl)benzamide, A-1a, (0.335g, 1 mmol) in 5 mL anhydrous DMF under an argon purge was added cesiumcarbonate (0.814 g, 2.5 mmol). The resulting suspension was stirred at˜65° C. for 17 hr. The mixture was allowed to cool to room temperatureand then was partitioned between ethyl acetate (50 mL) and water (75mL). The aqueous layer was extracted twice with ethyl acetate (50 mL)and the combined organics were washed with brine (25 mL), dried overNa₂SO₄, and concentrated to dryness. The crude residue was purified onsilica gel using a gradient of 0% to 6% methanol in 1:1 ethylacetate:hexane as eluent to obtainN-(3,4,5-trimethoxyphenyl)-3-[(pyrazin-2-yl)sulfanyl-methyl]benzamide asa pale yellow oil (0.18 g, 43%) which crystallized upon standing: mp112-119° C.; ¹H NMR (DMSO-d₆) δ 10.13 (s, 1H), 8.63 (d, 1H, J=1.55 Hz),8.53 (dd, 1H, J=2.60, 1.58 Hz), 8.36 (d, 1H, J=2.64 Hz), 8.00 (s, 1H),7.83 (d, 1H, J=7.81 Hz), 7.64 (d, 1H, J=7.72 Hz), 7.47 (t, 1H, J=7.7Hz), 7.21 (s, 2H), 4.56 (s, 2H), 3.77 (s, 6H), 3.65 (s, 3H). Anal.calc'd for C₂₁H₂₁N₃O₄S.0.2 MTBE: C, 61.58; H, 5.50; N, 9.79; S, 7.47.Found: C, 61.34; H, 5.43; N, 9.69; S, 7.34.

EXAMPLE A-2N-(3,4,5-Trimethoxyphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide

[0148]

[0149] Example A-2 was prepared in a similar manner to that describedfor A-1, except that 3-amino-5-mercapto-1,2,4-triazole (Aldrich) wasused in place of 2-pyrazinethiol in step (b): ¹H NMR (DMSO-d₆) δ 11.96(br s, 1H), 10.12 (s, 1H), 7.95 (s, 1H), 7.82 (d, 1H, J=7.8 Hz), 7.59(d, 1H, J=7.6 Hz), 7.46 (t, 1H, J=7.69 Hz), 7.23 (s, 2H), 6.05 (br s,2H), 4.32 (s, 2H), 3.78 (s, 6H), 3.65 (s, 3H); HR MS (FAB): Calculatedfor C₁₉H₂₂N₅O₄S (M+H⁺): 416.1393. Found: 416.1408. Anal. calc'd forC₁₉H₂₁N₅O₄S.0.3 EtOAc: C, 54.90; H, 5.34; N, 15.85; S, 7.26. Found: C,54.87; H, 5.50; N, 15.71; S, 7.03.

EXAMPLE A-3N-(4-Isopropyl-3-methylphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]-Benzamide

[0150]

[0151] Example A-3 was prepared in a similar manner to that describedfor A-1, except that 3-methyl-4-isopropylaniline hydrochloride(Maybridge) was used in place of 3,4,5-trimethoxyaniline in step (a): mp69-73° C.; ¹H NMR (DMSO-d₆) δ 10.07 (s, 1H), 8.62 (d, 1H, J=1.6 Hz),8.52 (dd, 1H, J=2.6, 1.6 Hz), 8.35 (d, 1H, J=2.6 Hz), 7.99 (s, 1H), 7.83(d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.7 Hz), 7.56-7.51 (m, 2H), 7.46 (t,1H, J=7.7 Hz), 7.20 (d, 1H, J=8.3 Hz), 4.55 (s, 2H), 3.10-3.05 (m, 1H),2.69 (s, 3H), 1.17 (d, 6H, J=6.9 Hz). Anal. calc'd for C₂₂H₂₃N₃OS.0.2MTBE: C, 69.91; H, 6.48; N, 10.64; S, 8.12. Found: C, 70.03; H, 6.40; N,10.41; S, 7.81.

EXAMPLE A-4N-(4-Isopropyl-3-methylphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]Benzamide

[0152]

[0153] Example A-4 was prepared in a similar manner to that describedfor A-1, except that 3-methyl-4-isopropylaniline was used in place of3,4,5-trimethoxyaniline in step (a), and3-amino-5-mercapto-1,2,4-triazole was used in place of 2-pyrazinethiolin step (b): ¹H NMR (DMSO-d₆) δ 11.93 (br s, 1H), 10.05 (s, 1H), 7.92(s, 1H), 7.80 (d, 1H, J=7.8 Hz), 7.57-7.51., (m, 3H), 7.43 (t, 1H, J=7.7Hz), 7.19 (d, 1H, J=8.3 Hz), 6.02 (br s, 2H), 4.30 (s, 2H), 3.09-3.04(m, 1H), 2.29 (s, 3H), 1.17 (d, 6H, J=6.9 Hz). Anal. calc'd forC₂₀H₂₃N₅OS.0.1 MTBE: C, 63.08; H, 6.25; N, 17.94; S, 8.22. Found: C,62.78; H, 6.26; N, 17.78; S, 8.00.

EXAMPLE A-5N-(4-Isopropyl-3-methylphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]Benzamide

[0154]

[0155] Example A-5 was prepared in a similar manner to that describedfor A-1, except that 3-methyl-4-isopropylaniline was used in place of3,4,5-trimethoxyaniline in step (a), and4-mercapto-1H-pyrazolo[3,4-d]pyrimidine was used in place of2-pyrazinethiol in step (b): mp 187-189° C.; ¹H NMR (DMSO-d₆) δ 10.09(s, 1H), 8.81 (s, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.85 (d, 1H, J=7.9Hz), 7.69 (d, 1H, J=7.7 Hz), 7.55-7.47 (m, 3H), 7.20 (d, 1H, J=8.4 Hz),4.78 (s, 2H), 3.09-3.06 (m, 1H), 2.29 (s, 3H), 1.18 (d, 6H, J=6.9 Hz).Anal. calc'd for C₂₃H₂₃N₅OS: C, 66.16; H, 5.55; N, 16.77; S, 7.68.Found: C, 65.90; H, 5.51; N, 16.98; S, 7.40.

EXAMPLE A-6N-(2-Methylquinolin-6-yl)-3-[(pyrazin-2-yl)sulfanylmethyl]Benzamide

[0156]

[0157] Example A-6 was prepared in a similar manner to that describedfor A-1, except that 6-amino-2-methylquinoline (Lancaster) was used inplace of 3,4,5-trimethoxyaniline in step (a): mp 133-135° C.; ¹H NMR(DMSO-d₆) δ 10.51 (s, 1H), 8.63 (s, 1H), 8.53 (t, 1H, J=1.9 Hz), 8.44(t, 1H, J=3.0 Hz), 8.35 (d, 1H, J=2.6 Hz), 8.20 (d, 1H, J=2.4 Hz), 8.04(s, 1H), 7.96 (d, 1H, J=9.0 Hz), 7.89 (d, 2H, J=9.1 Hz), 7.66 (d, 1H,J=7.7 Hz), 7.50 (t, 1H, J=7.7 Hz), 7.38 (d, 1H, J=8.4 Hz), 4.57 (s, 2H),2.63 (s, 3H). Anal. calc'd for C₂₂H₁₈N₄OS: C, 68.37; H, 4.69; N, 14.50;S, 8.30. Found: C, 68.41; H, 4.72; N, 14.52; S, 8.30.

EXAMPLE A-7N-(3-Isopropylphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]Benzamide

[0158]

[0159] Example A-7 was prepared in a similar manner to that describedfor A-1, except that 3-isopropylaniline (Maybridge) was used in place of3,4,5-trimethoxyaniline in step (a): ¹H NMR (DMSO-d₆) δ 10.02 (s, 1H),8.63 (d, 1H, J=1.6 Hz), 8.52 (dd, 1H, J=2.42, 1.5 Hz), 8.34 (d, 1H,J=2.6 Hz), 7.99 (s, 1H), 7.83 (d, 1H, J=7.7 Hz), 7.63-7.60 (m, 3H), 7.46(t, 1H, J=7.7 Hz), 7.25 (t, 1H, J=7.8 Hz), 6.97 (d, 1H, J=7.6 Hz), 4.55(s, 2H), 2.88-2.85 (m, 1H), 1.21 (d, 6H, J=6.9 Hz). Anal. calc'd forC₂₁H₂₁N₃OS.0.3 MTBE: C, 69.31; H, 6.36; N, 10.78; S, 8.22. Found: C,69.34; H, 6.15; N, 10.54; S, 7.96.

EXAMPLE A-8N-(3,5-Dibromo-4-methylphenyl)-3-[(pyrazin-2-yl)sulfanyl-methyl]Benzamide

[0160]

[0161] Example A-8 was prepared in a similar manner to that describedfor A-1, except that 3,5-dibomo-4-methylaniline (Lancaster) was used inplace of 3,4,5-trimethoxyaniline in step (a): mp 119-127° C.; ¹H NMR(DMSO-d₆) δ 10.39 (s, 1H), 8.61 (d, 1H, J=1.30 Hz), 8.51 (t, 1H, J=2.1Hz), 8.34 (d, 1H, J=2.61 Hz), 8.12 (s, 2H), 7.99 (s, 1H), 7.82 (d, 1H,J=7.96 Hz), 7.65 (d, 1H, J=7.73 Hz), 7.48 (t, 1H, J=7.74 Hz), 4.54 (s,2H), 2.47 (s, 3H). Anal. calc'd for C₁₉H₁₅N₃₄S.0.25 EtOAc: C, 46.62; H,3.33; N, 8.16; S, 6.22. Found: C, 46.33; H, 3.24; N, 7.90; S, 5.83.

EXAMPLE B-1N-(3,4,5-Trimethoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]Benzamide

[0162]

[0163] To a solution of 3,4,5-trimethoxyaniline (400 mg, 2.18 mmol) andtriethylamine (0.30 mL, 2.18 mmol) in dichloromethane was added 0.31 mL(2.18 mmol) of 3-chloromethylbenzoyl chloride (Aldrich). After 10 min,the solvent was removed and the residual crudeN-(3,4,5-trimethoxyphenyl)-3-(chloromethyl)benzamide, A-1a, wasdissolved in DMF (10 mL) under argon. To the resulting solution wasadded 4-mercapto-1H-pyrazolo[3,4-d]pyrimidine (332 mg, 2.18 mmol)followed by triethylamine (0.30 mL, 2.18 mmol). The resulting solutionwas heated at 70° C. for 2 h, then cooled and poured into water. Thesolid was collected by filtration and washed with water. Afterair-drying, the solid was sequentially triturated with ethylacetate/hexane and with dichloromethane, and the solid collected byfiltration to provide 360 mg (37%) ofN-(3,4,5-trimethoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl)benzamide,B-1: ¹H NMR (300 MHz, DMSO-d₆) δ 14.12 (s, 1H), 10.15 (s, 1H), 8.79 (s,1H), 8.03 (s, 1H), 7.83 (d, 1H, J=7.7 Hz), 7.68 (d, 1H, J=7.7 Hz), 7.48(t, 1H, J=7.7 Hz), 7.20 (s, 2H), 4.77 (s, 2H), 3.75 (s, 6H), 3.62 (s,3H). Anal. calc'd for C₂₂H₂₁N₅O₄S.0.7H₂O: C, 56.93; H, 4.87; N, 15.09;S, 6.91. Found: C, 56.89; H, 4.76; N, 14.85; S, 6.91.

EXAMPLE B-2N-(3,4,5-Trimethoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]Benzamide

[0164]

[0165] Example B-2 was prepared in a similar manner to that describedfor B-1, except that 5-amino-2-methoxypyridine was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.10 (s, 1H),10.20 (s, 1H), 8.75 (s, 1H), 8.43 (d, J=2.5 Hz, 1H), 8.25 (s, 1H),7.95-8.00 (m, 2H), 7.81 (d, 1H, J=7.8 Hz), 7.65 (d, 1H, J=7.7 Hz),7.41-7.46. (dd, 1H), 6.78 (d, 1H, J=8.8 Hz), 4.70 (s, 2H), 3.80 (s, 3H);APCIMS m/z 393 [M+H]⁺.

EXAMPLE B-3N-(Quinolin-6-yl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanyl-methyl]Benzamide

[0166]

[0167] Example B-3 was prepared in a similar manner to that describedfor B-1, except that 6-aminoquinoline was used in place of3,4,5-trimethoxyaniline: mp 236-240° C. (dec); ¹H NMR (DMSO-d₆) δ 14.15(s, 1H), 10.60 (s, 1H), 8.80 (s, 2H), 8.52 (s, 1H), 8.34-8.29 (m, 2H),8.10 (s, 1H), 8.05-7.98 (m, 2H), 7.91 (d, 1H, J=7.7 Hz), 7.72 (d, 1H,J=7.4 Hz), 7.54-7.48 (m, 2H), 4.79 (s, 2H). Anal. calc'd forC₂₂H₁₆N₆OS.0.7H₂O: C, 62.16; H, 4.13; N, 19.77; S, 7.54. Found: C,62.34; H, 3.83; N, 19.48; S, 7.61.

EXAMPLE B-4N-(5-Methylisoxazol-3-yl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]Benzamide

[0168]

[0169] Example B-4 was prepared in a similar manner to that describedfor B-1, except that 3-amino-5-methylisoxazole was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 13.99 (s, 1H),11.34 (s, 1H), 8.79 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.90 (d, 1H,J=8.0 Hz), 7.72 (d, 1H, J=8.0 Hz), 7.47 (dd, 1H, J=7.5, 7.6 Hz), 6.74(s, 1H), 4.76 (s, 2H), 2.41 (s, 3H); APCIMS m/z 367 [M+H]⁺.

EXAMPLE B-5N-(Pyridin-4-yl)methyl-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]Benzamide

[0170]

[0171] Example B-5 was prepared in a similar manner to that describedfor B-1, except that 4-picolylamine was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.05 (s, 1H),9.08-9.12 (t, 1H, J=5.8 Hz), 8.74 (s, 1H), 8.44 (d, 1H, J=5.7 Hz), 8.25(s, 1H), 7.96 (s, 1H), 7.76 (d, 1H, J=7.9 Hz), 7.62 (d, 1H, J=7.7 Hz),7.40 (dd, 1H, J=7.7, 7.9 Hz), 7.24 (d, 1H, J=5.7 Hz), 4.70 (s, 2H), 4.43(d, 2H, J=5.9 Hz); APCIMS m/z 377 [M+H]⁺.

EXAMPLE B-6N-(1,3-Benzodioxyl-5-ylmethyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]Benzamide

[0172]

[0173] Example B-6 was prepared in a similar manner to that describedfor B-1, except that 3,4-(methylenedioxy)benzylamine was used in placeof 3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.05 (s, 1H),8.98 (t, 1H, J=6.0 Hz), 8.78 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.77(d, 1H, J=7.9 Hz), 7.64 (d, 1H, J=7.5 Hz), 7.42 (dd, 1H, J=7.6, 7.9 Hz),6.84-6.87 (m, 2H), 6.78 (d, 1H, J=7.9 Hz), 5.97 (s, 2H), 4.74 (s, 2H),4.36 (d, 2H, J=6.1 Hz); APCIMS m/z 420 [M+H]⁺.

EXAMPLE B-7N-(2-Methoxybenzyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]Benzamide

[0174]

[0175] Example B-7 was prepared in a similar manner to that describedfor B-1, except that 2-methoxybenzylamine was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.12 (s, 1H), 8.86(t, 1H, J=6.0 Hz), 8.79 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.81 (d,1H, J=7.9 Hz), 7.64 (d, 1H, J=7.6 Hz), 7.44 (dd, 1H, J=7.6, 7.9 Hz),7.23 (m, 1H), 7.16 (d, 1H, J=7.2 Hz), 6.98 (d, 1H, J=7.9 Hz), 6.89 (dd,1H, J=7.5, 6.8 Hz), 4.75 (s, 2H), 4.43 (d, 2H, J=6.1 Hz), 3.82 (s, 3H);APCIMS m/z 406 [M+H]⁺.

EXAMPLE B-8N-(2-Phenylethyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]Benzamide

[0176]

[0177] Example B-8 was prepared in a similar manner to that describedfor B-1, except that phenethylamine was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s, 1H), 8.79(s, 1H), 8.61 (t, 1H J=5.7 Hz), 8.30 (s, 1H), 7.93 (s, 1H), 7.70 (d, 1H,J=7.9 Hz), 7.62 (d, 1H, J=7.9 Hz), 7.41 (dd, 1H, J=7.6, 7.9 Hz),7.16-7.31 (m, 5H), 4.73 (s, 2H), 3.43-3.50 (m, 2H), 2.83 (dd, 2H, J=7.2,7.9 Hz); APCIMS m/z 390 [M+H]⁺.

EXAMPLE B-9N-(2-Methoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]Benzamide

[0178]

[0179] Example B-9 was prepared in a similar manner to that describedfor B-1, except that 2-methoxyaniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.12 (s, 1H), 9.43(s, 1H), 8.81 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.87 (d, 1H, J=7.9Hz), 7.77 (d, 1H, J=7.5 Hz), 7.70 (d, 1H, J=7.9 Hz), 7.48 (dd, 1H,J=7.5, 7.6 Hz), 7.19 (m, 1H), 7.09 (d, 1H, J=7.2 Hz), 6.97 (dd, 1H,J=7.1, 8.0 Hz), 4.79 (s, 2H), 3.83 (s, 3H); APCIMS in/z 392 [M+H]⁺.

EXAMPLE B-10N-[3-(N-Methyl-N-phenylamino)propyl]-3-[(5-methyl-1H-1,2,4-triazol-3-yl)sulfanylmethyl]Benzamide

[0180]

[0181] Example B-10 was prepared in a similar manner to that describedfor B-1, except that N-(3-aminopropyl)-N-methylaniline was used in placeof 3,4,5-trimethoxyaniline, and 3-mercapto-5-methyl-1H-1,2,4-triazolewas used in place of 4-mercapto-1H-pyrazolo[3,4-d]pyrimidine: ¹H NMR(300 MHz, CD₃OD) δ 7.80 (s, 1H), 7.68 (d, 1H, J=7.9 Hz), 7.52 (d, 1H,J=7.5 Hz), 7.38 (dd, 1H, J=7.5, 8.0 Hz), 7.15 (m, 2H), 6.74-6.77 (m,2H), 6.64 (dd, 1H, J=7.1, 7.1 Hz).4.36 (s, 2H), 3.41-3.45 (m, 4H), 2.93(s, 3H), 2.38 (s, 3H), 1.85-1.96 (m, 2H); APCIMS m/z 396 [M+H]⁺.

EXAMPLE B-11N-(1,3-Benzodioxyl-5-ylmethyl)-3-[(5-methyl-1H-1,2,4-triazol-3-yl)sulfanylmethyl]Benzamide

[0182]

[0183] Example B-11 was prepared in a similar manner to that describedfor B-1, except that (3,4-methylenedioxy)benzylamine was used in placeof 3,4,5-trimethoxyaniline, and 3-mercapto-5-methyl-1H-1,2,4-triazolewas used in place of 4-mercapto-1H-pyrazolo[3,4-d]pyrimidine: ¹H NMR(300 MHz, CD₃OD) δ 7.83 (s, 1H), 7.71 (d, 1H, J=7.5 Hz), 7.52 (d, 1H,J=7.2 Hz), 7.38 (dd, 1H, J=7.50, 7.6 Hz), 6.76-6.86 (m, 3H), 5.93 (s,2H), 4.47 (s, 2H), 4.35 (s, 2H), 2.38 (s, 3H); APCIMS m/z 383 [M+H]⁺.

EXAMPLE B-12N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl-sulfanyl)methyl]Benzamide

[0184]

[0185] Example B-12 was prepared in a similar manner to that describedfor B-1, except that 4-cyano-3-trifluoromethylaniline was used in placeof 3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.07 (s, 1H),10.98 (s, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 8.26-8.31 (m, 2H), 8.15 (d,1H, J=7.9 Hz), 8.08 (s, 1H), 7.89 (d, 1H, J=7.5 Hz), 7.76 (d, 1H, J=7.9Hz), 7.53 (dd, 1H J=7.50, 7.9 Hz), 4.79 (s, 2H); APCIMS m/z 455 [M+H]⁺.

EXAMPLE B-13N-(3,3-Diphenylpropyl)-3-{[(5-methyl-1H-1,2,4-triazol-3-yl)-sulfanyl]Methyl}Benzamide

[0186]

[0187] Example B-13 was prepared in a similar manner to that describedfor B-1, except that 3,3-diphenyl-1-propylamine was used in place of3,4,5-trimethoxyaniline, and 3-mercapto-5-methyl-1H-1,2,4-triazole wasused in place of 4-mercapto-1H-pyrazolo[3,4-d]pyrimidine: ¹H NMR (300MHz, CD₃OD) δ 7.74 (s, 1H), 7.62 (d, 1H, J=7.6 Hz), 7.50 (d, 1H, J=7.6Hz), 7.25-7.38 (m, 9H), 7.13-7.18 (m, 2H), 4.35 (s, 2H), 4.05 (dd, 1H,J=7.6, 7.9 Hz), 3.34-3.37 (m, 2H), 2.38 (m, 5H); APCIMS m/z 443 [M+H]⁺.

EXAMPLE B-143-{[(5-Methyl-1H-1,2,4-triazol-3-yl)-sulfonyl]methyl}-N-phenethylbenzamide

[0188]

[0189] Example B-14 was prepared in a similar manner to that describedfor B-1, except that 2-phenylethylamine was used in place of3,4,5-trimethoxyaniline, and 3-mercapto-5-methyl-1H-1,2,4-triazole wasused in place of 4-mercapto-1H-pyrazolo[3,4-d]pyrimidine: ¹H NMR (300MHz, CD₃OD) δ 7.78 (s, 1H), 7.64 (d, 1H, J=7.9 Hz), 7.51 (d, 1H, J=7.5Hz), 7.38 (dd, 1H, J=7.5, 7.9 Hz), 7.18-7.33 (m, 5H), 4.35 (s, 2H),3.57-3.62 (m, 2H), 2.90-2.93 (m, 2H), 2.40 (s, 3H); APCIMS m/z 353[M+H]⁺.

EXAMPLE B-153-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-isopropylphenyl)-benzamide

[0190]

[0191] Example B-15 was prepared in a similar manner to that describedfor B-1, except that 3-isopropylaniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s, 1H),10.19 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.85 (d, 1H,J=7.9 Hz), 7.69 (d, 1H, J=7.9 Hz), 7.61 (m, 2H), 7.48 (dd, 1H, J=7.6,7.6 Hz), 7.25 (dd, 1H, J=7.5, 8.0 Hz), 6.99 (d, 1H, J=7.9 Hz), 4.78 (s,2H), 2.83-2.91 (m, 1H), 1.21 (d, 6H, J=6.0 Hz); APCIMS m/z 404 [M+H]⁺.

EXAMPLE B-163-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-trifluoromethyl-5-methoxyphenyl)-benzamide

[0192]

[0193] Example B-16 was prepared in a similar manner to that describedfor B-1, except that 3-trifluoromethyl-5-trifluoromethoxyaniline wasused in place of 3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ14.13 (s, 1H), 10.51 (s, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H),7.86 (d, 1H, J=7.9 Hz), 7.81 (s, 1H), 7.73 (m, 2H), 7.50 (dd, 1H,J=7.50, 8.0 Hz), 6.98 (s, 2H), 6.46-6.50 (m, 1H), 4.78 (s, 2H), 3.83 (s,3H); APCIMS m/z 460 [M+H]⁺.

EXAMPLE B-173-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3,5-bis-trifluoromethylphenyl)-benzamide

[0194]

[0195] Example B-17 was prepared in a similar manner to that describedfor B-1, except that 3,5-bis(trifluoromethyl)aniline was used in placeof 3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.20 (s, 1H),10.92 (s, 1H), 8.87 (s, 1H), 8.57 (s, 2H), 8.37 (s, 1H), 8.17 (s, 1H),7.97 (d, 1H, J=7.9 Hz), 7.89 (s, 1H), 7.83 (d, 1H, J=7.6 Hz), 7.60 (dd,1H, J=7.50, 8.0 Hz), 4.86 (s, 2H); APCIMS m/z 498 [M+H]⁺.

EXAMPLE B-183-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-t-butylphenyl)-benzamide

[0196]

[0197] Example B-18 was prepared in a similar manner to that describedfor B-1, except that 3-(tert-butyl)aniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s, 1H),10.19 (s, 1H), 8.81 (s, 1H), 8.30 (s, 2H), 8.05 (s, 1H), 7.85-7.88 (d,1H, J=7.6 Hz), 7.75 (s, 1H), 7.65-7.71 (m, 1H), 7.48 (dd, 1H, J=7.6, 7.9Hz), 7.26 (dd, 1H, J=7.5, 8.0 Hz), 7.13 (d, 1H, J=7.9 Hz), 4.78 (s, 2H),1.29 (s, 9H); APCIMS t/z 418 [M+H]⁺.

EXAMPLE B-193-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-isopropylphenyl)-benzamide

[0198]

[0199] Example B-19 was prepared in a similar manner to that describedfor B-1, except that 4-isopropylaniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s, 1H),10.19 (s, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.84 (d, 1H,J=7.6 Hz), 7.64-7.70 (m, 3H), 7.47 (dd, 1H, J=7.5, 8.0 Hz), 7.21 (d, 2H,J=8.3 Hz), 4.78 (s, 2H), 2.81-2.90 (m, 1H), 1.19 (d, 6H, J=6.0 Hz);APCIMS m/z 404 [M+H]⁺.

EXAMPLE B-203-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-trifluoromethoxyphenyl)-benzamide

[0200]

[0201] Example B-20 was prepared in a similar manner to that describedfor B-1, except that 3-trifluoromethoxyaniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s, 1H),10.54 (s, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H),7.86 (d, 1H, J=7.6 Hz), 7.71-7.78 (m, 2H), 7.46-7.53 (m, 2H), 7.09 (d,1H, J=8.3 Hz), 4.79 (s, 2H); APCIMS m/z 446 [M+H]⁺.

EXAMPLE B-213-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3,5-dimethylphenyl)-benzamide

[0202]

[0203] Example B-21 was prepared in a similar manner to that describedfor B-1, except that 3,5-dimethylaniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s, 1H),10.10 (s, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.83-7.85 (d,1H, J=7.5 Hz), 7.68-7.71 (d, 1H, J=7.6 Hz), 7.45-7.50 (dd, 1H, J=7.50,7.6 Hz), 7.39 (s, 2H), 6.74 (s, 1H), 4.78 (s, 2H), 2.26 (s, 6H); APCIMSm/z 390 [M+H]⁺.

EXAMPLE B-223-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-(2-hydroxyethyl)phenyl)-benzamide

[0204]

[0205] Example B-22 was prepared in a similar manner to that describedfor B-1, except that 3-(1-hydroxyethyl)aniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s, 1H),10.23 (s, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 8.06 (m, 1H), 7.86 (d, 1H,J=7.9 Hz), 7.73 (s, 1H), 7.74-7.84 (m, 2H), 7.48 (dd, 1H, J=7.6, 7.9Hz), 7.27 (dd, 1H, J=7.9, 8.0 Hz), 7.06 (d, 1H, J=7.9 Hz), 5.18 (d, 1H,J=3.0), 4.78 (s, 2H), 4.68 (q, 1H), 1.32 (d, 3H, J=9.0 Hz); APCIMS n/z406 [M+H]⁺.

EXAMPLE B-233-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-dimethylaminophenyl)-benzamide

[0206]

[0207] Example B-23 was prepared in a similar manner to that describedfor B-1, except that 4-dimethylaminoaniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) 13.76 (s, 1H), 9.63(s, 1H), 8.44 (s, 1H), 7.94 (s, 1H), 7.66 (s, 1H), 7.46 (d, 1H, J=7.9Hz), 7.301 (d, 1H, J=7.5 Hz), 7.18 (d, 1H, J=9.0 Hz), 7.10 (dd, 1H,J=7.5, 7.6 Hz), 6.35 (d, 1H, J=9.0 Hz), 4.56 (s, 2H), 2.13 (s, 6H);APCIMS m/z 405 [M+H]⁺.

EXAMPLE B-243-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-trifluoromethylsulfonylphenyl)-benzamide

[0208]

[0209] Example B-24 was prepared in a similar manner to that describedfor B-1, except that 3-(trifluoromethylsulfonyl)aniline was used inplace of 3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s,1H), 10.83 (s, 1H), 8.80 (s, 1H), 8.66 (s, 1H), 8.35-8.39 (m, 1H), 8.30(s, 1H), 8.09 (s, 1H), 7.90 (d, 1H, J=7.9 Hz), 7.85 (m, 2H), 7.75 (d,1H, J=7.60), 7.53 (dd, 1H, J=7.5, 7.6 Hz), 4.79 (s, 2H); APCIMS m/z 494[M+H]⁺.

EXAMPLE B-253-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-dimethylaminophenyl)-benzamide

[0210]

[0211] Example B-25 was prepared in a similar manner to that describedfor B-1, except that 3-dimethylaminoaniline was used in place of3,4,5-trimethoxyaniline: ¹H NMR (300 MHz, DMSO-d₆) 14.14 (s, 1H), 10.06(s, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.84 (d, 1H, J=8.0Hz), 7.680 (d, 1H, J=7.5 Hz), 7.46 (dd, 1H, J=7.5, 7.6 Hz), 7.20 (s,1H), 7.13 (m, 2H), 6.46-6.50 (m, 1H), 4.78 (s, 2H), 2.89 (s, 6H); APCIMSm/z 405 [M+H]⁺.

EXAMPLE B-26

[0212] (a) To an array of 40 μL of 0.25 M solution of different amines(0.01 mmol) in acetonitrile distributed in the eleven columns of a96-well plate was added 40 μL of 0.25 M solution of triethylamine (0.01mmol) and the array of reactions was agitated briefly. To each of thewells was added 40 μL of a 0.25 M solution of 3-(chloromethyl)benzoylchloride (0.01 mmol) in acetonitrile and the plate was agitatedin a shaker at room temperature for 2 h.

[0213] (b) An 0.25 M solution of different mercapto compounds wasprepared in DMF and 40 μL (0.01 mmol) and was added in eight differentrows to the appropriate intermediate from step (a) above. To eachreaction mixture was add approximately 8-15 mg of cesium carbonate andthe reactions were heated at 60° C. on a Vortex heater for 16 h. Thesolvents were removed using the SpeedVac™ apparatus and the crudereaction mixtures were redissolved in DMSO and transferred using aliquid handler to a 1 mL 96-well plate to give a final theoreticalconcentration of 10 mM.

EXAMPLE B-27

[0214] Using the general procedure described above in Example B-26, thefollowing compounds were made (wherein for convenience, and asunderstood in the art, not all hydrogen atoms have been expresslyindicated as bonding to each carbon and/or nitrogen atom).

EXAMPLE C-13-[(5-Cyanoamino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]-N-(3,4,5-trimethoxyphenyl)Benzamide

[0215]

[0216] To a suspension of 0.300 g (0.73 mmol) ofN-(3,4,5-trimethoxyphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide,A-2, in 10 mL THF was added ethanol until the mixture becamehomogeneous. The mixture was cooled to 0° C. and 4-methylmorpholine(0.095 ml, 0.86 mmol) was added followed by cyanogen bromide (0.115 g,1.08 mmol) in one portion. After stirring at 0 to 20° C. over 2 h, themixture was partitioned between ethyl acetate (50 mL) and brine (50 mL).The aqueous layer was extracted twice with ethyl acetate (50 mL) and thecombined organics were washed with brine (25 mL), dried over Na₂SO₄, andconcentrated to dryness. The crude residue was triturated with a mixtureof MTBE, ethyl acetate, and hexanes to yield the desired product as apale yellow solid (0.27 g, 85%) that was collected by filtration:mp>165° C. (dec); ¹H NMR (DMSO-d₆) δ 10.14 (s, 1H), 8.19 (s, 1H), 7.96(s, 1H), 7.84 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.7 Hz), 7.49 (t, 1H,J=7.7 Hz), 7.18 (s, 2H), 4.39 (s, 2H), 3.77 (s, 6H), 3.69 (s, 3H). Anal.calc'd for C₂₀H₂₀N₆O₄S.0.3 EtOAc: C, 54.53; H, 4.84; N, 18.00; S, 6.87.Found: C, 54.86; H, 4.83; N, 17.91; S, 6.64.

EXAMPLE C-23-[(5-(Methoxycarbonylamino)-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]-N-(3,4,5-Trimethoxyphenyl)Benzamide

[0217]

[0218] To a suspension of 0.154 g (0.37 mmol) ofN-(3,4,5-trimethoxyphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide,A-2, in dichloromethane (5 mL) at room temperature was added DMF untilthe mixture became homogeneous. To the mixture was addedN-methylmorpholine (0.075 mL, 0.7 mmol) followed by methyl chloroformate(0.050 mL, 0.65 mmol). After stirring room temperature for 2 h, themixture was partitioned between MTBE (50 mL) and brine (50 mL). Theaqueous layer was extracted with 1:1 MTBE/ethyl acetate (2×50 mL) andthe combined organics were washed with brine (25 mL), dried over Na₂SO₄,and concentrated to dryness. The crude residue was triturated with MTBEand filtered. The solid was triturated a second time with MTBE/ethylacetate to yieldN-(3,4,5-trimethoxyphenyl)-3-[(5-methylcarbamoyl-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide, C-2, as a white solid (0.13 g, 74%): mp>150°C. (dec); ¹H NMR (DMSO-d₆) δ 10.10 (s, 1H), 7.97 (s, 1H), 7.84 (d, 1H,J=7.7 Hz), 7.61 (d, 1H, J=7.7 Hz), 7.48-7.45 (m, 2H), 7.21 (s, 2H), 4.38(s, 2H), 3.90 (s, 3H), 3.77 (s, 6H), 3.64 (s, 3H). Anal. calc'd forC₂₁H₂₃N₅O₆S.0.75H₂O: C, 51.79; H, 5.07; N, 14.38; S, 6.58. Found: C,52.13; H, 5.29; N, 14.11; S, 6.17.

EXAMPLE C-3N-(3,4,5-Trimethoxyphenyl)-3-[(5-acetylamino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]Benzamide

[0219]

[0220] To a solution of 0.15 g (0.37 mmol) ofN-(3,4,5-trimethoxyphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide,A-2, in acetic acid (5 mL) at room temperature was added aceticanhydride (0.200 mL, 2.1 mmol). After stirring at room temperature for1.5 hr, the mixture was added dropwise to a cold solution of phosphatebuffer (1M, pH 7, 60 mL). The resulting precipitate was collected byfiltration, washed with water, and dried under vacuum. The dried solidwas triturated with MTBE/ethyl acetate and filtered to yieldN-(3,4,5-trimethoxyphenyl)-3-[(5-acetylamino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide, C-3, as a white solid (0.12 g, 71%): mp196-201° C.; ¹H NMR (DMSO-d₆) δ 10.14 (s, 1H), 8.02 (s, 1H), 7.85 (d,1H, J=7.8 Hz), 7.65 (d, 1H, J=7.8 Hz), 7.49 (t, 1H, J=7.7 Hz), 7.22 (s,2H), 4.40 (s, 2H), 3.78 (s, 6H), 3.65 (s, 3H), 2.50 (s, 3H, obscured byDMSO). Anal. calc'd for C₂₁H₂₃N₅O₅S.0.9H₂O: C, 53.24; H, 5.28; N, 14.78;S, 6.77. Found: C, 53.28; H, 4.98; N, 14.48; S, 6.68.

EXAMPLE D-1N-(4-Isopropyl-3-methylphenyl)-3-[(pyrazin-2-yl)methyl-sulfanyl]Benzamide

[0221]

[0222] (a) A suspension of methylpyrazine (5 g, 53 mmol) andN-bromosuccinimide (9.45 g, 53 mmol) in carbon tetrachloride (200 mL)was heated at reflux while exposed to a 100 watt light source. After 4hr, the dark mixture was allowed to cool to room temperature and wasdecanted. The supernatant was filtered and the filtrate reduced to ˜25mL volume then passed through silica gel using a gradient of 0% to 5%ethyl acetate in CHCl₃. Decomposition was evident upon concentration ofchromatographed product. The residue was taken up in CH₂Cl₂, washed withwater, dried over sodium sulfate, and concentrated cold. Unstable oily2-(bromomethyl)pyrazine, D-1a, (2 g, 22%) was used quickly in nextreaction: ¹H NMR (CDCl₃) δ 8.72 (s, 1H), 8.55 (d, 1H, J=1.8 Hz), 8.51(d, 1H, J=2.5 Hz), 4.56 (s, 2H).

[0223] (b) 3-[(Pyrazin-2-yl)methylsulfanyl]benzoic acid, D-1b, wasprepared in a manner similar to that described in example A-1, step (b):mp 131-135° C.

[0224] (c) To a solution of 3-[(pyrazin-2-yl)methylsulfanyl]benzoicacid, D-1b, (0.15 g, 0.61 mmol), 4-isopropyl-3-methylanilinehydrochloride (0.113 g, 0.61 mmol), and triethylamine (0.09 mL, 0.65mmol) in 2 mL DMF at room temperature was added EDC (0.116 g, 0.61mmol). After stirring at room temperature for 24 hr, the mixture waspartitioned between ethyl acetate (30 mL) and brine (30 mL). The aqueouslayer was extracted twice with ethyl acetate (30 mL) and the combinedorganics were washed twice with water (20 mL), once with brine(25 mL),dried over sodium sulfate, and concentrated to dryness. The residue wasfiltered through silica gel using 10% methanol in chloroform and thenpurified by radial chromatography with a 2 mm rotor using a gradient of0% to 50% ethyl acetate in hexanes as eluent to yieldN-(4-isopropyl-3-methylphenyl)-3-[(pyrazin-2-yl)methylsulfanyl]benzamide,D-1, as a pale amber oil (0.09 g, 35%): ¹H NMR (DMSO-d₆) δ 10.10 (s,1H), 8.68 (s, 1H), 8.57 (d, 1H, J=1.6 Hz), 8.51 (d, 1H, J=2.4 Hz), 7.92(s, 1H), 7.76 (d, 1H, J=7.7 Hz), 7.59 (d, 1H, J=7.9 Hz), 7.55 (d, 1H,J=8.3 Hz), 7.52 (d, 1H, J=1.9 Hz), 7.46 (t, 1H, J=7.8 Hz), 7.21 (d, 1H,J=8.4 Hz), 4.50 (s, 2H), 3.11-3.05 (m, 1H), 2.30 (s, 3H), 1.18 (d, 6H,J=6.8 Hz). Anal. calc'd for C₂₂H₂₃N₃OS.0.4H₂O: C, 68.68; H, 6.24; N,10.92; S, 8.33. Found: C, 68.86; H. 6.11; N, 10.70; S, 8.23

EXAMPLE D-2N-(2-Methylquinolin-6-yl)-3-[(pyrazin-2-yl)methylsulfanyl]Benzamide

[0225]

[0226] Example D-2 was prepared in a similar manner to that describedfor D-1, except that 6-amino-2-methylquinoline was used in place of4-isopropyl-3-methylaniline in step (c): mp 102-105° C.; ¹H NMR(DMSO-d₆) δ 10.53 (s, 1H), 8.69 (s, 1H), 8.57 (d, 1H, J=1.3 Hz), 8.52(d, 1H, J=2.4 Hz), 8.46 (s, 1H), 8.22 (d, 1H, J=8.4 Hz), 7.80-7.97 (m,2H), 7.91 (d, 1H, J=9.1 Hz), 7.82 (d, 1H, J=7.8 Hz), 7.63 (d, 1H, J=7.8Hz), 7.51 (d, 1H, J=7.8 Hz), 7.40 (d, 1H, J=8.5 Hz), 4.52 (s, 2H), 2.65(s, 3H). Anal. calc'd for C₂₂H₁₈N₄OS.0.3H₂O.0.2 EtOAc: C, 66.87; H,4.97; N, 13.68; S, 7.83. Found: C, 66.77; H, 5.18; N, 13.40; S, 7.61.

EXAMPLE D-3N-(2-Methyl-quinolin-6-yl)-3-(pyridin-3-ylmethylsulfanyl)-benzamideDihydrochloride

[0227]

[0228] Example D-3 was prepared in a similar manner to that describedfor D-1, except that 3-picolyl chloride was used in place of2-(bromomethyl)pyrazine in step (b), and 6-amino-2-methylquinoline wasused in place of 4-isopropyl-3-methylaniline in step (c): HPLCR_(t)=12.2 min.; TLC R_(f)=0.4 (5% methanol/chloroform); ¹H NMR (500MHz, DMSO-d₆ w/ D₂O) δ 8.95 (d, 1H, J=8.6 Hz), 8.77-8.73 (m, 2H), 8.66(dd, 1H, J=1.1, 5.5 Hz), 8.41-8.33 (m, 2H), 8.20 (d, 1H, J=9.2 Hz),7.97-7.83 (m, 4H), 7.66-7.53 (m, 2H), 4.51 (s, 2H), 2.94 (s, 3H); ¹³CNMR (75 MHz, DMSO-d₆ w/ D₂O) δ 167.8, 158.4, 146.8, 146.4, 144.5, 143.8,140.5, 139.5, 136.7, 136.6, 136.4, 134.9, 131.7, 130.5, 130.4, 129.2,128.4, 128.2, 126.0, 122.7, 119.0, 35.2, 22.3; MS (ESI) m/z 386 [M+H]⁺.Anal. calc'd for C₂₃H₁₉N₃O₂S.2HCl 0.3 H₂O: C, 59.56; H, 4.69; N, 9.06;S, 6.91. Found: C, 59.56; H, 4.66; N, 9.00; S, 6.82.

EXAMPLE E-1N-(2-methyl-quinolin-6-yl)-3-[{5-(phenylamino)-2-H-pyrazol-3-yl}methylsulfanyl]Benzamide

[0229]

[0230] (a) To a solution of 3-thiobenzoic acid (5.0 g, 32.4 mmol) in 150mL of acetone was added cesium carbonate (22.2 g, 68.1 mmol) and2-chloro-N-methoxy-N-methylacetamide (4.9 g, 35.7 mmol). After stirringfor 1 h, the reaction was quenched with dropwise addition of 1N HCl. Thereaction mixture was partitioned between 100 mL of ethyl acetate and 50m]L of 1N HCl, dried over sodium sulfate, and evaporated. The residuewas chromatographed on silica gel using 33% hexane/66% ethyl acetate/1%acetic acid to afford2-[(3-carboxyphenyl)sulfanyl]-N-methoxy-N-methylacetamide, E-1a, as awhite solid 8.5 g (96%). ¹H NMR (500 MHz, CDCl₃) δ 8.15 (t, 1H, J=1.5Hz), 8.06 (br s, 1H), 7.92 (dt, 1H, J=7.8, 1.2 Hz), 7.68 (dq, 1H, J=6.0,1.2 Hz), 3.88 (s, 2H), 3.74 (s, 3H), 3.22 (s, 3H).

[0231] (b) To a solution of2-[(3-carboxyphenyl)sulfanyl]-N-methoxy-N-methylacetamide, E-1a, (0.84g, 3.1 mmol) and EDC (0.66 g, 3.4 mmol) in 10 mL of THF was added6-amino-2-methylquinoline (0.54 g, 3.4 mmol). After 3 h, the solutionwas concentrated and the residue was purified by column chromatographywith 1:2 hexane/ethyl acetate to afford3-[(N-methoxy-N-methylcarbamoyl)methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide,E-1b, as a white crystalline solid 0.89 g (72%): ¹H NMR (500 MHz, CDCl₃)δ 8.50 (br s, 1H), 8.45 (d, 1H, J=1.2 Hz), 8.05-7.97 (m, 3H), 7.73 (dd,1H, J=7.8, 1.5 Hz), 7.57 (dt, 1H, J=13.4, 4.8 Hz), 7.56 (d, 1H, 4.5 Hz),7.39 (t, 1H, J=4.5 Hz), 7.27 (d, 1H, J=4.8 Hz), 3.88 (s, 2H), 3.80 (s,3H), 3.24 (s, 3H), 2.71 (s, 3H); MS (ESI): Calculated for C₂₁H₂₁N₃O₃S(M+H⁺): 395. Found: 395. Anal. calc'd for C₂₀H₂₄N₂O₆S.0.2H₂O: C, 63.20;H, 5.41; N, 10.53; S, 8.03. Found: C, 63.03; H, 5.32; N, 10.35; S, 7.92.

[0232] (c) To a solution of thioacetanilide (0.30 g, 1.95 mmol) in 10 mLof anhydrous THF at −78° C. was added n-BuLi (1.56 mL, 3.89 mmol, 2.5 Min hexane) over a 5 min period. The mixture was warmed to 0° C. for 1 h,then recooled to −78° C. To this solution was added a solution of3-[(N-methoxy-N-methylcarbamoyl)methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide,E-1b, (0.35 g, 0.89 mmol) in 5 mL in THF, and the resulting solution waswarmed to 0° C. After 1 h, a solution of 1:1 methanol:acetic acid (1.0mL) was added dropwise over 1 min. The reaction solution was partitionedbetween 30 mL of MTBE and extracted with 1N hydrochloric acid (2×20 mL)and saturated brine (1×30 mL), and the organic layer was dried oversodium sulfate and concentrated to give a yellow oil. Purification usingcolumn chromatography with 3:1 hexane/ethyl acetate affordedN-(2-methyl-quinolin-6-yl)-[2-oxo-3-phenylthiocarbamoyl-propylsulfanyl]benzamide,E-1c, as a pale yellow foam 0.25 g (56%): ¹H NMR (500 MHz, CDCl₃) δ 8.66(br s, 1H), 8.26 (br s, 1H), 7.94-7.85 (3H, m), 7.81 (br s, 1H),7.71-7.66 (m, 2H), 7.51 (br s, 1H), 7.45-7.41 (m, 1H), 7.26-7.21 (m 4H),7.13-7.10 (m, 1H), 3.50 (br s, 2H), 2.67 (s, 3H), 2.03 (s, 2H); MS(ESI): Calculated for C₂₇H₂₃N₃O₂S₂ (M+H⁺): 486 Found: 486.

[0233] (d) To a solution containingN-(2-methyl-quinolin-6-yl)-[2-oxo-3-phenylthiocarbamoyl-propylsulfanyl]benzamide,E-1c, in 4 mL of ethanol was added acetic acid (0.038 mL, 0.67 mmol)followed by hydrazine monohydrate (0.032 mL, 0.63 mmol). The solutionwas stirred for 2 h, then concentrated to give the crude product as anamber oil. Purification by radial chromatography (1 mm silica plate)with 90% ethyl acetate/10% methanol as eluant afforded a tan solid.Precipitation of product from dichloromethane by dropwise addition ofhexane gave 0.12 g (58%) ofN-(2-methyl-quinolin-6-yl)-3-[{5-(phenylamino)-2-H-pyrazol-3-yl}methylsulfanyl]benzamide,E-1, as a white solid: mp 172-174° C. HPLC Rt=13.51 min.; ¹H NMR (500MHz, Acetone-d₆) δ 8.40-8.38 (m, 1H), 8.01 (d, 1H, J=8.5 Hz), 7.91 (s,1H), 7.86 (dd, 1H, J=8.0, 1.2 Hz), 7.76 (t, 2H, J=9.5 Hz), 7.47 (d, 1H,J=8.0 Hz), 7.35 (t, 1H, J=7.5 Hz), 7.24 (d, 1H, J=8.5 Hz), 7.16 (br s,2H), 7.02 (t, 2H, J=7.0 Hz), 6.59 (t, 1H, J=7.0 Hz), 5.73 (s, 1H), 4.18(s, 2H), 2.52 (s, 3H); HRMS (FAB): Calculated for C₂₇H₂₃N₅OS (M+H⁺):466.1702. Found: 466.1715. Anal. calc'd for C₂₇H₂₃N₅OS.0.5 CH₂Cl₂: C,65.05; H, 4.76; N, 13.79; S, 6.31. Found C, 64.94; H, 4.72; N, 13.47; S,6.51.

EXAMPLE E-2N-(3,4,5-trimethoxyphenyl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]Benzamide

[0234]

[0235] Example E-2 was prepared in a similar manner to that describedfor E-1, except that 3,4,5-trimethoxyaniline was used in place of6-amino-2-methylquinoline in step (b): mp 67-69° C. ¹H NMR (500 MHz,CDCl₃) δ 8.20 (br s, 1H), 7.75 (br s, 1H), 7.64 (d, 1H, J=7.8 Hz), 7.42(d, 1H, J=7.2 Hz), 7.29 (t, 1H, J=7.5 Hz), 6.96-6.91 (m, 3H), 6.83 (t,1H, J=7.2 Hz), 5.89 (s, 1H), 4.05 (s, 2H), 3.80 (s, 3H), 3.75 (s, 6H);HRMS (FAB): Calculated for C₂₆H₂₆N₄O₄S (M+H⁺): 491.1753 Found: 491.1737.Anal. calc'd for C₂₆H₂₆N₄O₄S.0.4 Et₂O: C, 63.72; H, 5.81; N, 10.77; S,6.16. Found: C, 63.47; H, 5.88; N, 10.52; S, 6.34.

EXAMPLE F-13-[{5-((E)-2-(4-Hydroxy-3-methoxyphenyl)ethenyl)-2H-pyrazol-3-yl}-methylsulfanyl]-N-(2-methylquinolin-6-yl)Benzamide

[0236]

[0237] (a) To 5 mL of ethanol was added(E)-4-(4-hydroxy-3-methoxy-phenyl)-but-3-en-2-one (0.50 g, 2.60 mmol), 1g of 4 Å molecular sieves, acetic acid (0.16 mL, 2.60 mmol), andhydrazine carboxylic acid t-butyl ester (0.34 g, 2.60 mmol). Afterstirring for 18 h, the mixture was filtered and the filtrate wasconcentrated to give a crude product as a tan solid, which waschromatographed on silica with 2:1 hexane/ethyl acetate to furnishN-[3-(4-hydroxy-3-methoxy-phenyl)-1-methyl-(E)-2-propenylidene]hydrazinecarboxylicacid t-butyl ester, F-1a, 0.68 g (86%) as a white solid. TLC Rf=0.45(40% hexane/60% ethyl acetate). ¹H NMR (500 MHz, CDCl₃) δ 7.87 (br s,1H), 7.11-7.08 (m, 2H), 6.98-6.52 (m, 2H), 6.89 (d, 1H, J=8.0 Hz), 5.82(br s, 1H), 3.93 (s, 3H), 2.13 (s, 3H), 1.53 (s, 9H); LRFAB: Calculatedfor C₁₆H₂₂N₂O₄ (M+H⁺): 307. Found: 307.

[0238] (b) To a solution ofN-[3-(4-hydroxy-3-methoxy-phenyl)-1-methyl-(E)-2-propenylidene]-hydrazinecarboxylicacid t-butyl ester, F-1a, (0.50 g, 1.63) in 5 mL of dichloromethane wasadded diisopropylethylamine (64 mL, 3.92 mmol) andchlorotriisopropylsilane (0.77 mL, 3.59 mmol). After 20 h, the mixturewas concentrated and the residue was partitioned between 30 mL of MTBEand saturated sodium bicarbonate (2×30 mL). The organic layer was filterthrough 10 g of silica and concentrated to afford a yellow oil.Purification was accomplished using chromatotron with a 2 mm rotoreluting with 80% hexane/20% ethyl acetate to give 0.48 g (65%) ofN-{3-[4-methoxy-3-(triisopropyl-silanyloxy)-phenyl]-1-methyl-(E)-2-propenylidene]hydrazinecarboxylicacid t-butyl ester, F-1b, as a white solid: TLC Rf=0.82 (60% hexane/40%ethyl acetate); ¹H NMR (500 MHz, CDCl₃) δ 7.47 (br s, 1H), 7.02 (d, 1H,J=1.5 Hz), 6.94 (d, 1H, J=16.5 Hz), 6.87 (dd, 1H, J=8.3 Hz, 1.5 Hz),6.82 (d, 1H, J=8.0 Hz), 6.77 (d, 1H, J=16.5 Hz), 3.81 (s, 3H), 2.02 (s,3H), 1.50 (s, 9H), 1.29-1.23 (m, 3H), 1.09 (d, 18H, J=7.0 Hz); LRFAB:Calculated for C₂₅H₄₂N₂O₄Si (M+H⁺): 463; Found: 463.

[0239] (c) To a −78° C. solution ofN-[3-[4-methoxy-3-(triisopropylsilanyloxy)-phenyl]-1-methyl-(E)-2-propenylidene]hydrazinecarboxylicacid t-butyl ester, F-1b, (0.33 g, 0.72 mmol) in 10 mL of anhydrous THFwas added n-BuLi (0.61 mL, 3.89 mmol, 2.5 M in hexane) over 5 minutes.After the addition was complete, the mixture was warmed to 0° C. for 1 hand then recooled to −78° C. To the resulting mixture was added asolution of3-[(N-methoxy-N-methylcarbamoyl)methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide,E-1b, (0.14 g, 0.36 mmol) in 5 mL in THF, and the resulting mixture waswarmed to 0° C. After 1 h, the reaction was cooled to −78° C. andquenched by adding 1:1 acetic acid:methanol (1 mL). The reaction mixturewas then partitioned between 30 mL of MTBE and 1 N aq. HCl (2×20 mL).The organic layer was dried over sodium sulfate and concentrated to givea yellow oil. Purification by silica gel chromatography, with 2:1hexane/ethyl acetate as eluant, afforded 0.12 g (43%) ofN²-[1-{4-methoxy-3-(triisopropylsilanyloxy)-phenyl)-6-{3-(2-methyl-quinolin-6-ylcarbamoyl)phenylsulfanyl}-5-oxo-(E)-hex-1-en-3-ylidene]-hydrazinecarboxylicacid t-butyl ester, F-1c, as a pale yellow foam: TLC R_(f)=0.50 (60%ethyl acetate/hexane); ¹H NMR (500 MHz, CDCl₃) δ 8.64 (s, 1H), 8.12-8.10(m, 2H), 8.03 (br s, 1H), 7.90 (d, 1H, J=8.0 Hz), 7.77 (d, 2H, J=7.0Hz), 7.46 (t, 1H, J=8.0 Hz), 7.31 (d, 1H, J=5.0 Hz), 6.91-6.78 (m, 5H),3.92-3.60 (m, 4H), 2.73 (s, 3H), 1.54-1.43 (m, 3H), 1.20 (s, 9H), 1.07(d, 18H, J=9.5 Hz).

[0240] (d) To a solution of 0.10 g (0.14 mmol) ofN²-[1-{4-methoxy-3-(triisopropylsilanyloxy)-phenyl}-6-{3-(2-methyl-quinolin-6-ylcarbamoyl)phenylsulfanyl}-5-oxo-(E)-hex-1-en-3-ylidene]-hydrazinecarboxylicacid t-butyl ester, F-1c, in 5 mL of dichloromethane was added 5 mL oftrifluoroacetic acid. After 1 h, the reaction mixture was concentrated,5 mL of toluene added, and the solvent removed again to give an amberoil. The residue was purified by silica gel chromatography with 1:1:1hexane/dichloromethane/ethyl acetate as eluant to give 0.089 g (92%) of3-[{5-{(E)-2-(3-methoxy-4-triisopropylsilanyloxyphenyl)ethenyl}-2H-pyrazol-3-yl}methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide,F-1d, as tan solid: TLC Rf=0.18 (50% ethyl acetate/hexane); ¹H NMR (300MHz, Acetone-d₆) δ 10.21 (br s, 1H), 8.95 (d, 1H, J=1.5 Hz), 8.71 (d,1H, J=8.4 Hz), 8.43-8.31 (m, 3H), 8.10 (d, 1H, J=7.5 Hz), 7.88-7.82 (m,2H), 7.85 (t, 1H, J=7.8 Hz), 7.41-7.19 (m, 4H), 7.11 (d, 1H, J=8.1 Hz),6.69 (s, 1H), 4.57 (s, 2H), 4.10 (s, 3H), 3.05 (s, 3H), 1.57-1.47 (m,3H), 1.34 (d, 18H, J=8.5 Hz); MS (ESI): Calculated for C₃₉H₄₆N₃OSi(M+H⁺): 678; Found: 678.

[0241] (e) To a solution of3-[{5-{(E)-2-(3-methoxy-4-triisopropylsilanyloxyphenyl)ethenyl}-2H-pyrazol-3-yl}methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide,F-1d, (0.057 g, 0.084 mmol) in 5 mL THF was added tetrabutylammoniumfluoride (1M) in tetrahydrofuran (0.093 mL, 06092 mmol). After 3 h, thesolution was concentrated and the residue was partitioned between 20 mLof ethyl acetate and 20 mL of 1M phosphate buffer at 7.0 pH. The organiclayer was filtered through 10 g of silica with 50 mL dichloromethane andconcentrated to give the crude product as an amber oil. The residue wasfurther purified by radial chromatography on a 1 mm plate with 3:1hexane/ethyl acetate as eluant. The purified product was dissolved in 1mL of dichloromethane and hexane was added dropwise to precipitate 0.34g (77%) of3-[{5-((E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl)-2H-pyrazol-3-yl}methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide, F-1, as a whitesolid: HPLC Rt=13.12 min.; TLC Rf=0.30 (50% ethyl acetate/hexane); ¹HNMR (500 MHz, CDCl₃) δ 9.67 (br s, 1H), 8.41 (br s, 1H), 8.03 (d, 1H,J=8.5 Hz), 7.89-7.87 (m, 2H), 8.79 (d, 1H, J=9.0 Hz), 7.71 (d, 1H, J=7.5Hz), 7.33 (t, 1H, J=8.0 Hz), 7.25 (d, 1H, J=8.5 Hz), 7.01 (s, 1H), 6.78(d, 1H, J=16.5 Hz), 6.83-6.78 (m, 2H), 6.67 (d, 1H, J=8 Hz), 6.29 (s,1H), 4.19 (s, 2H), 3.74 (s, 3H), 2.53 (s, 3H). HRMS (FAB): Calculatedfor C₃₀H₂₆N₄O₃S (M+H⁺): 655.0780 Found: 655.0804. Anal. calc'd forC₃₀H₂₆N₄O₃S.0.8 EtOAc: C, 67.23; H, 5.51; N, 9.45; S, 5.41. Found: C,67.08; H, 5.60; N, 9.73; S, 5.45.

EXAMPLE F-23-[5-(2-(3,4-Dimethoxyphenyl)ethenyl)-2H-pyrazol-3-yl)methylsulfanyl]-N-(2-methylquinolin-6-yl)Benzamide

[0242]

[0243] Example F-2 was prepared in a similar manner to that describedfor F-1, except that acetophenone was used in place of4-(4-hydroxy-3-methoxy-phenyl)-but-3-en-2-one in step (a), and theprotection/deprotection steps (b) and (e) were not needed: mp 99-101°C.; TLC Rf=0.50 (75% dichloromethane/25% ethyl acetate); HPLC Rt=14.04min.; ¹H NMR (500 MHz, CDCl₃) δ 8.33 (br s, 1H), 8.21 (d, 1H, J=2.0 Hz)7.95 (br s, 1H), 7.80 (d, 1H, J=8.5 Hz), 7.75 (d, 1H, J=9.1 Hz), 7.70(d, 1H, J=7.5 Hz), 7.61 (d, 2H, J=7.5 Hz), 7.51 (dd, 1H, J=9.3, 2.5 Hz),7.43 (d, 1H, J=8.0 Hz), 7.32-7.25 (m, 5H), 7.15 (d, 8.5 Hz), 6.57 (s,1H), 4.26 (s, 2H), 2.61 (s, 3H). HRMS (FAB): Calculated for C₂₇H₂₂N₄OS(M+H⁺): 451.1593. Found: 451.1580.

[0244] Anal. calc'd for C₂₇H₂₂N₄OS.0.8 EtOAc: C, 70.42; H, 5.30; N,11.33; S, 6.48. EtOAc Found: C, 70.39; H, 5.34; N, 11.29; S, 6.48.

EXAMPLE F-33-(2-{5-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-2H-pyrazol-3-yl}-ethyl)-N-(3-methyl-4-isopropylphenyl)-benzamide

[0245]

[0246] Example F-3 was prepared in a similar manner to that describedfor F-1, except that (E)-4-(3,4-dimethoxyphenyl)-but-3-en-2-one was usedin place of (E)-4-(4-hydroxy-3-methoxyphenyl)-but-3-en-2-one in step(a),N-(4-isopropyl-3-methyl-phenyl)-3-[2-(N-methoxy-N-methylcarbamoyl)-ethyl]benzamide,G-1f, (from Example G-1, step (f)) was used in place of3-[(N-methoxy-N-methylcarbamoyl)methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide,E-1b, in step (c) and the protection/deprotection steps (b) and (e) werenot needed: HPLC Rt=16.37 min.; ¹H NMR (300 MHz, CDCl₃) δ 7.71 (br s,1H), 7.69-7.66 (m, 2H), 7.44-7.17 (m, 5H), 7.01-6.81 (m, 5H), 6.25 (s,1H), 3.89 (d, 6H, J=1.5 Hz), 3.12-3.01 (m, 5H), 2.32 (s, 3H), 1.20 (d,6H, J=5.1 Hz); HRMS (FAB): Calculated for m/z C₃₂H₃₅N₃O₃ (M+Cs⁺):642.1733, Found: 642.1712. Anal. calc'd for C₃₂H₃₅N₃O₃: C, 75.42; H,6.92; N, 8.24. Found C, 75.45; H, 7.08; N, 8.16.

EXAMPLE F-44-Fluoro-3-[{5-((E)-1-propenyl)-2H-pyrazol-3-yl}methoxy]-N-[4-(pyrrolidin-1-yl)-3-trifluoromethylphenyl]Benzamide

[0247]

[0248] Example F-4 was prepared in a similar manner to that describedfor F-1, except that (E)-3-penten-2-one was used in place of(E)-4-(4-hydroxy-3-methoxyphenyl)-but-3-en-2-one in step (a),4-fluoro-N-[4-(pyrrolidin-1-yl)-3-trifluoromethylphenyl]-3-[2-(N-methoxy-N-methylcarbamoyl)methoxy]benzamide,(prepared in a similar manner as described for4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethyl-phenyl]-3-[(N-methoxy-N-methylcarbamoyl)methoxy]benzamide,J-1d, in Example J-1) was used in place of3-[(N-methoxy-N-methylcarbamoyl)methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide,E-1b, in step (c) and the protection/deprotection steps (b) and (e) werenot needed: HPLC Rt=16.27 min. ¹H NMR (300 MHz, CDCl₃) δ 7.75 (m, 4H),7.45 (d, 1H, J=8.7 Hz), 7.42-7.37 (m, 1H), 7.35-7.28 (m, 2H), 7.15 (t,1H, J=8.4 Hz), 7.00 (d, 1H, J=8.7 Hz), 6.56 (d, 1H, J=8.9 Hz), 6.37 (s,1H), 6.27-6.15 (m, 2H), 5.60 (s, 1H), 5.23 (s, 1H), 3.30-3.29 (m, 4H),1.98-1.95 (m, 4H), 1.92 (d, 3H, J=6.3 Hz); MS (ESI): m/z Calculated forC₂₁H₂₄F₄N₄O₂ (M+H⁺): 489, Found:489.

[0249] Anal. calc'd for C₂₅H₂₄F₄N₄O₂: C, 61.47; H, 4.95; N, 11.47. FoundC, 61.32; H, 5.06; N 11.33.

EXAMPLE F-53-(2-{5-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-2H-pyrazol-3-yl}-ethyl)-N-(3-methyl-4-isopropylphenyl)-benzamide

[0250]

[0251] Example F-5 was prepared in a similar manner to that describedfor F-3, except that (E)-4-(pyridin-3-yl)-3-buten-2-one was used inplace of (E)-4-(3,4-dimethoxyphenyl)-but-3-en-2-one in step (a), and4-[4-(t-butoxycarbonyl)piperazin-1-yl]-3-trifluoromethylaniline,prepared according to the procedure described in WO 99/21845 (p. 58) forthe preparation of 1-methyl-4-(4-nitrophenyl)piperazine, was used inplace of 4-isopropyl-3-methylaniline in step (d) of Example G-1, and thefinal deprotection step (e) was carried out in a manner similar to thatdescribed in Example G-10: HPLC Rt=13.53 min.; ¹H NMR (300 MHz, DSMO-d₆)δ 8.69 (s, 1H), 8.44 (d, 1H, J=3.3 Hz), 8.14 (s, 1H), 8.07-7.82 (m, 2H),7.86 (s, 1H), 7.81-7.79 (m, 1H), 7.54-7.43 (m, 3H), 7.39-7.37 (m, 1H),7.25-7.04 (m, 2H), 310-2.98 (m, 4H), 2.83-2.78 (m, 8H); HRMS (FAB):Calculated for C₃₀H₂₉F₃N₆O (M+H⁺): 547.2433 Found: 547.2445. Anal.calc'd for C₂₈H₃₀N₄O.0.5H₂O.0.2 CH₂Cl₂: C, 63.35; H 5.35; N, 14.68.Found C, 63.26; H, 5.38; N, 14.25.

EXAMPLE G-1N-(4-Isopropyl-3-methyl-phenyl)-3-{2-[5-(4-(methylsulfamoyl)-phenylamino)-2H-pyrazol-3-yl]-ethyl}-benzamide

[0252]

[0253] (a) To a solution of 4-acetylamino-benzenesulfonyl chloride (2.00g, 8.56 mmol) in 25 mL of DMF was added 4-dimethylaminopyridine (0.11 g,0.86 mmol) and diphenylaminomethane (1.79 mL, 10.27 mmol). After 4 h,the reaction mixture was added to 125 mL of water, and the precipitatewas collected by filtration, washed with diethyl ether (2×20 mL), thendried under high vacuum for 4 h to afford 1.98 g (61%) ofN-(diphenylmethyl)-4-(acetylamino)benzenesulfonamide, G-1a: HPLCRt=12.90 min.; ¹H NMR (500 MHz, CDCl₃) δ 10.20 (br s, 1H), (8.82 (d, 1H,J=2.0 Hz), 7.57 (s, 4H), 7.24-7.20 (m, 8H), 7.18-7.13 (m, 2H), 5.58-7.52(m, 1H), 3.38 (s, 3H); LRFAB: Calculated for C₂₁H₂₀N₂O₃S (M+H⁺): 381Found:381.

[0254] (b) To DMF (15 mL) was addedN-(diphenylmethyl)-4-(acetylamino)benzenesulfonamide, G-1a, (1.50 g,3.94 mmol), potassium carbonate (1.37 g, 9.86 mmol), and iodomethane(0.37 mL, 5.93 mmol). The reaction mixture was stirred for 3 h at 60°C., cooled to 25° C., and partitioned between 50 mL of MTBE and 1N HCl(2×50 mL). The organic layer was dried over sodium sulfate andconcentrated to give an amber oil, which was purified by chromatographyon silica gel (3:1 hexane:ethyl acetate) to give 1.50 g (98%) ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)benzenesulfonamide, G-1b: TLCRf=0.62 40% hexane/ethyl acetate; ¹H NMR (300 MHz, CDCl₃) δ 7.67-7.64(m, 1H), 7.58-7.52 (m, 2H), 7.28-7.23 (m, 8H), 7.21-7.08 (m, 3H), 6.47(s, 1H), 2.68 (s, 3H), 2.20 (s, 3H).

[0255] (c) To a solution of 2.00 g, (5.30 mmol) ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)-benzenesulfonamide, G-1b, intoluene (30 mL) was added2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(1.07 g, 2.64 mmol). The solution was warmed to 100° C. for 2 h thencooled to 25° C. The reaction mixture was filtered through a silica gelplug using 50 mL of MBTE and concentrated. The residue was purified bychromatography on silica gel (5:1 hexane/ethyl acetate) to afforded 1.62g (77%) of 4-[N-(diphenylmethyl)-N-methylsulfamoyl]-thioacetanilide,G-1c, as a yellow oil: HPLC Rt=18.67 min.; ¹H NMR (300 MHz, CDCl₃) δ7.84 (d, 1H, J=8.7 Hz), 7.72 (d, 1H, J=8.5 Hz), 7.28-7.25 (m, 8H),7.09-7.07 (m, 2H), 6.46 (s, 1H), 2.77 (s, 3H), 2.56 (s, 3H).

[0256] (d) To a solution of 5.00 g (33.26 mmol) 3-formylbenzoic acid indichloromethane at 0° C. was added oxalyl chloride (3.48 mL, 39.92 mmol)and DMF (0.01 mL). The reaction was stirred for 3 h at 25° C., and thenconcentrated to dryness. The residue (2.1 g, 12.45 mmol) was dissolvedin dichloromethane (30 mL) and 4-isopropyl-3-methylaniline.HCl (2.55 g,13.70 g) added, followed by diisopropylethylamine (4.48 mL). Afterstirring for 2 h, the solution was washed with sat. sodium bicarbonate(2×20 mL) and 1N HCl (2×20 mL) and the organic layer dried over sodiumsulfate and concentrated to dryness. The residue was purified on silicagel (3:1 hexane:ethyl acetate) to provide 2.99 g (90%) of3-formyl-N-(4-isopropyl-3-methylphenyl)benzamide, G-1d, as a off-whitesolid: ¹H NMR (300 MHz, CDCl₃) δ 10.12 (s, 1H), 8.60-8.58 (m, 1H),8.38-8.36 (m, 1H), 8.21-8.15 (m, 2H), 8.07-8.04 (m, 1H), 7.93 (br s,1H), 7.71-7.67 (m, 1H), 7.44 (br s, 1H), 7.27-7.24 (s, 1H), 3.15-3.10(m, 1H), 2.35 (s, 3H), 1.23 (d, 6H, J=6.7 Hz).

[0257] (e) To a solution of 2-diethyl (N-methoxy-Nmethyl-carbamoylmethyl)phosphonate (1.70 mL, 7.82 mmol) in 15 ml of THFat −78° C. was added sodium bis(trimethylsilyl)amide (9.24 mL, 1M inTHF) dropwise over 2 min. After the addition was complete, the reactionwas warmed to 0° C. for 1 h. To this solution was added a solution of2.00 g (7.11 mmol) of3-formyl-N-(4-isopropyl-3-methyl-phenyl)-benzamide, G-1d, in 20 mL ofTHF. The solution was stirred for 1 h, then quenched with 1:1 MeOH/AcOH(1 mL). The mixture was partitioned between 50 mL of ethyl acetate and1N HCl (2×20 mL), and the organic layer was dried over sodium sulfateand concentrated. The residue was purified on silica gel (2:1hexane:ethyl acetate) and to afford 1.33 g (51%) ofN-(4-isopropyl-3-methylphenyl)-3-[(E)-2-(N-methoxy-N-methylcarbamoyl)ethenyl]-benzamide,G-1e, as a white solid foam: ¹H NMR (300 MHz, CDCl₃) δ 8.10 (br s, 1H),7.83-7.79 (m, 2H), 7.73-7.68 (m, 2H), 7.52-7.45 (m, 3H), 7.28-7.24 (m,1H), 7.12 (d, 1H, J=15.9 Hz), 3.78 (s, 3H), 3.31 (s, 3H), 3.15-3.10 (m,1H), 2.36 (s, 3H), 1.23 (d, 6H, J=6.0 Hz).

[0258] (f) A mixture of 0.90 g (2.46 mmol)N-(4-isopropyl-3-methylphenyl)-3-[(E)-2-(N-methoxy-N-methylcarbamoyl)ethenyl]-benzamide,G-1e, and 0.1 g of 10% palladium on carbon in 20 ml of 1:1 MeOH:EtOAcwas stirred under 1 atm H₂ for 18 h. The reaction was filtered though a0.5 uM teflon filter and concentrated to give 0.90 g (100%) ofN-(4-isopropyl-3-methylphenyl)-3-[2-(N-methoxy-N-methylcarbamoyl)ethyl]-benzamide,G-1f: ¹H NMR (300 MHz, CDCl₃) δ 7.74 (s, 2H), 7.68 (d, 1H, J=4.2 Hz),7.44-7.40 (m, 4H), 7.25-7.23 (m, 1H), 3.63 (s, 3H), 3.18 (s, 3H),3.14-3.11 (m, 1H), 3.06-3.03 (m, 2H), 2.79 (t, 2H, J=4.5 Hz), 2.36 (s,3H), 1.22 (d, 6H, J=4.2 Hz).

[0259] (g) To a solution of 0.45 g (1.34 mmol) of4-[N-(diphenylmethyl)-N-methylsulfamoyl]thioacetanilide, G-1c, and 0.16mL (1.34 mmol) of N,N′-dimethylpropyleneurea (DMPU) in 15 mL of THF at−78° C. was added 1.07 mL (2.68 mmol) of 2.5 M n-BuLi in hexane. After0.25 h, the reaction was warmed to 0° C. for 0.5 h, then recooled to−78° C. To the reaction mixture was added a solution of 0.23 g (0.62mmol) ofN-(4-isopropyl-3-methylphenyl)-3-[2-(N-methoxy-N-methylcarbamoyl)ethyl]-benzamide,G-1f, in 5 mL of THF. The reaction was warmed to 0° C. for 1 hour andthen quenched by dropwise addition of 0.5 mL of 1:1 MeOH/AcOH. Themixture was partitioned between 30 mL of ethyl acetate and sat. sodiumbicarbonate (2×10 mL). The organic layer was dried over sodium sulfateand concentrated. The residue was purified by chromatography on silicagel (1:2 ethyl acetate:hexane) to afford 0.24 g (54%) of3-[4-{4-(N-(diphenylmethyl)-N-methylsulfamoyl)phenylthiocarbamoyl}-3-oxo-butyl]-N-(4-isopropyl-3-methylphenyl)benzamide,G-1 g, as an amber oil: ¹H NMR (500 MHz, CDCl₃) δ 7.91-7.83 (m, 2H),7.74-7.64 (m, 3H), 7.59-7.47 (m, 3H), 7.41-7.23 (m, 8H) 7.12-7.04 m,6H), 6.43 (s, 1H), 7.25-7.23, (m, 1H), 3.63 (s, 3H), 3.18 (s, 3H),3.18-3.13 (m, 1H), 3.11-3.01 (m, 2H), 2.83 (s, 2H), 2.78 (s, 3H),2.37-2.32 (m, 2H), 1.21 (d, 6H, 1.5 Hz).

[0260] (h) To a solution of 0.36 g (0.51 mmol) of3-[4-{4-(N-(diphenylmethyl)-N-methyl-sulfamoyl)phenylthiocarbamoyl}-3-oxo-butyl]-N-(4-isopropyl-3-methylphenyl)benzamide,G-1 g, in 5 ml of ethanol were added acetic acid (0.20 mL, 0.34 mmol)and hydrazine monohydrate (0.016 mL, 0.34 mmol). After 1 h, the solutionwas partitioned between ethyl acetate (30 mL) and 1N HCL (2×20 mL). Theorganic layer was washed with sat. sodium bicarbonate (2×20 mL), driedover sodium sulfate, and concentrated to give a yellow oil. Purificationby chromatography on silica gel (25% ethyl acteate:hexane) afforded 0.28g (79%) of3-{2-[5-(4-(N-(diphenylmethyl)-N-methylsulfamoyl)phenylamino}-2H-pyrazol-3-yl]ethyl}-N-(4-isopropyl-3-methyl-phenyl)-benzamide,G-1 h, as yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.09 (s, 1H), 7.67 (brs, 1H), 7.63 (d, 1H, J=7.5 Hz), 7.48-7.42 (m, 3H), 7.60-7.22 (m, 10H),7.01-7.04 (m, 3H), 7.01 (d, 2H, J=8.4 Hz), 6.43 (s, 1H), 5.78 (s, 1 h),3.13-3.04 (m, 1H), 2.93-2.84 (m, 4H), 2.61 (s, 3H), 2.28 (s, 3H), 1.19(d, 6H, J=6.6 Hz); MS (ESI): m/z Calculated for C₄₂H₄₃N₅O₃S (M−H⁻): 696Found 696.

[0261] (i) To a solution of3-{2-[5-{4-(N-(diphenylmethyl)-N-methylsulfamoyl)phenylamino}-2H-pyrazol-3-yl]ethyl}-N-(4-isopropyl-3-methyl-phenyl)-benzamide,G-1 h, in 0.025 mL of formic acid and 1.2 mL of acetic acid was added0.08 goof 10% palladium on carbon. The mixture was stirred at 80° C. for96 h, then cooled to room temperature and filtered though a 0.5 μMTeflon filter. The filtrate was concentrated and the residue waspurified by chromatography on silica gel (2:1 ethyl acetate:hexane) toaffordN-(4-isopropyl-3-methyl-phenyl)-3-{2-[5-(4-(N-methylsulfamoyl)phenylamino)-2H-pyrazol-3-yl]ethyl}benzamide,G-1, (0.053 g, 87%): HPLC Rt=14.65 min; ¹H NMR (Acetone-d₆) δ 791 (br s,1H), 7.59 (br s, 1H), 7.69 (d, 1H, J=6.0 Hz), 7.52-7.25 (m, 7H), 7.08(d, 1H, J=8.1 Hz), 3.51-2.89 (m, 5H), 2.40 (s, 3H), 2.19 (s, 3H), 1.08(d, 6H, J=6.9 Hz); HRMS (FAB): Calculated for C₂₉H₃₃N₅O₃S (M+H⁺):532.2382, Found: 532.2891

EXAMPLE G-2N-(2-Methylquinolin-6-yl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]Benzamide

[0262]

[0263] Example G-2 was made in a similar manner to that described forG-1, except that 6-amino-2-methylquinoline was used in place of4-isopropyl-3-methylaniline in step (d), and thioacetanilide was usedinstead of 4-[N-(diphenylmethyl)-N-methylsulfamoyl]thioacetanilide,G-1c, in step (g), and the final deprotection step (i) was not needed:mp 98-102° C. ¹H NMR (500 MHz, CDCl₃) δ 8.79 (d, 1H, J=2 Hz), 8.32 (brs, 1H), 7.95 (d, 1H, J=8.5 Hz), 7.92 (d, 1H, J=9.0 Hz), 7.22 (d, 1H,J=7.5 Hz), 6.74 (dd, 1H, J=9.0, 2.0 Hz), 7.37 (t, 1H, J=7.5 Hz),7.31-7.20 (m, 6H), 7.06 (d, 2H, J=8.0 Hz), 6.85 (t. 1H, J=7.5 Hz), 5.81(s, 1H), 2.96 (t, 2H, J=6.0 Hz), 2.91 (t, 2H, J=6.0 Hz) 2.65 (s, 3H);HRMS (FAB): Calculated for C₂₈H₂₅N₅O (M+H⁺): 448.2137 Found:448.2129.Anal. calc'd for C₂₈H₂₅N₅O.0.3 EtOAc: C, 73.99; H, 5.83; N, 14.78. FoundC, 73.72; H, 5.88; N, 14.78.

EXAMPLE G-3N-(4-isopropyl-3-methylphenyl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]Benzamide

[0264]

[0265] Example G-3 was made in a similar manner to that described forG-1, except thioacetanilide was used instead of4-[N-(diphenylmethyl)-N-methylsulfamoyl]thioacetanilide, G-1c, in step(g), and the final deprotection step (i) was not needed: mp 150-151° C.;¹H NMR (500 MHz, CDCl₃) δ 7.84 (s, 1H), 7.65 (d, 1H, J=7.5 Hz), 7.62 (s,1H), 7.42-7.35 (m, 3H), 7.36 (t, 1H, J=7.5 Hz), 7.28-7.17 (m, 4H), 7.05(d, 2H, J=8.5 Hz), 5.80 (s, 1H), 3.12-3.07 (m, 1H), 2.97 (t, 2H, J=7.5Hz), 2.90 (t, 2H, J=7.0 Hz), 2.30 (s, 3H); HRMS (FAB): Calculated forC₂₈H₃₀N₄O (M+H⁺): 439.2498 Found: 439.2488. Anal. calc'd forC₂₈H₃₀N₄O.0.1CH₂Cl₂ Found: C, 75.49; H 6.81; N, 12.53. Found C, 75.44;H, 6.81; N, 12.53.

EXAMPLE G-4N-(4-Isopropyl-3-methyl-phenyl)-3-{2-[5-(6-methoxypyridin-3-yl)Amino-2H-pyrazol-3-yl]-ethyl}-benzamide

[0266]

[0267] Example G-4 was made in a similar manner to that described forG-1, except that N-(6-methoxy-pyridin-3-yl)acetamide was used instead ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)-benzenesulfonamide, G-1b, instep (c). ¹H NMR (300 MHz, CDCl₃) δ 7.97 (d, 1H, J=2.7 Hz), 7.84 (br s,1H), 7.67-7.62 (m, 2H), 7.49 (dd, 1H, J=8.9, 3.0 Hz), 7.42-7.40 (m, 3H),7.30-7.61 (m, 2H), 7.19 (d, 1H, J=9.0 Hz), 5.66 (s, 1H), 3.88 (s, 3H),3.10 (q, 1H, J=6.6 Hz), 2.97-2.90 (m, 4H), 2.17 (s, 3H), 1.23 (d, 6H,J=4.2 Hz); HRMS (FAB): Calculated for C₂₈H₃₁N₅O₂ (M+H⁺): 470.2556,Found: 470.2563. Anal. calc'd for C₂₈H₃₃N₅O₂Cl₂: C, 61.99; H, 6.13; N,12.91. Found C, 61.83; H, 6.39; N, 12.83.

EXAMPLE G-5N-(4-Dimethylamino-3-trifluoromethylphenyl)-3-{2-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}-benzamide

[0268]

[0269] Example G-5 was made in a similar manner to that described forG-1, except that 4-(dimethylamino)-3-trifluoromethylaniline, preparedaccording to the procedure described in WO 99/21845 (p. 58) for thepreparation of 1-methyl-4-(4-nitrophenyl)piperazine, was used in placeof 4-isopropyl-3-methylaniline in step (d), andN-(6-methoxy-pyridin-3-yl)acetamide was used instead ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)-benzenesulfonamide, G-1b, instep (c): ¹H NMR (300 MHz, CDCl₃) δ 8.27 (br s, 1H), 7.93 (d, 1H, J=1.5Hz), 7.84 (dd, 1H, J=4.5, 1.5 Hz), 7.88 (d, 1H, J=2.7 Hz), 7.64 (d, 1H,J=5.7 Hz), 7.60 (s, 1H), 7.37 (dd, 1H, J=8.7, 3.0 Hz), 7.66 (d, 1H, 4.5Hz), 7.58 (s, 1H), 7.43 (dd, 1H, J=5.40, 1.5 Hz), 7.33 (t, 1H, J=4.8Hz), 7.29-7.26 (m, 2H), 6.63 (d, 1H, J=5.4 Hz), 5.62 (s, 1H) 3.86 (s,3H), 2.94-2.86 (m, 4H), 2.69 (s, 6H); HRMS (FAB): Calculated forC₂₇H₂₇F₃N₆O₂ (M+H⁺): 525.2226, Found: 525.2208. Anal. calc'd forC₂₇H₂₇F₃N₆O.0.5H₂O: C, 60.78; H, 5.29; N, 15.75. Found C, 61.15; H,5.25; N, 15.7

EXAMPLE G-6N-(6-Dimethylamino-5-trifluoromethylpyridin-3-yl)-3-{2-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}-benzamide

[0270]

[0271] Example G-6 was made in a similar manner to that described forG-1, except that 5-amino-2-(dimethylamino)-3-trifluoromethylpyridine,prepared according to the procedure described in WO 99/21845 (p. 58) forthe preparation of 1-methyl-4-(4-nitrophenyl)piperazine, was used inplace of 4-isopropyl-3-methylaniline in step (d), andN-(6-methoxy-pyridin-3-yl)acetamide was used instead ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)-benzenesulfonamide, G-1b, instep (c): HPLC Rt=14.04 min; ¹H NMR (300 MHz, CDCl₃) δ 8.73 (br s, 1H),8.47 (d, 1H, J=2.4 Hz), 8.18 (d, 1H, J=2.0 Hz), 7.88 (d, 1H, J=2.7 Hz),7.64 (d, 1H, J=5.7 Hz), 7.60 (s, 1H), 7.37 (dd, 1H, J=8.7, 3.0 Hz),7.29-7.21 (m, 2H), 6.58 (d, 1H, J=8.7 Hz), 5.78 (s, 1H), 3.83 (s, 3H),2.94 (s, 6H), 2.86-2.76 (m, 4H); HRMS (FAB): Calculated for C₂₆H₂₆F₃N₇O₃(M+H⁺): 526.2178, Found: 526.2194. Anal. calc'd for C₂₆H₂₆F₃N₇O₃.0.4Et₂O: C, 59.71; H, 5.45; N, 17.66. Found C, 59.58; H, 5.44; N, 17.53.

EXAMPLE G-7N-(3,5-Dichloro-4-dimethylaminophenyl)-3-{2-[5-(6-methoxy-pyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}Benzamide

[0272]

[0273] Example G-7 was made in a similar manner to that described forG-1, except that 3,5-dichloro-4-(pyrrolidino)aniline, prepared accordingto the procedure described in WO 99/21845 (p. 58) for the preparation of1-methyl-4-(4-nitrophenyl)piperazine, was used in place of4-isopropyl-3-methylaniline in step (d), andN-(6-methoxy-pyridin-3-yl)acetamide was used instead ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)-benzenesulfonamide, G-1b, instep (c): HPLC Rt=16.07 min; ¹H NMR (300 MHz, Acetone-d₆) δ 8.25 (d, 1H,J=2.7 Hz), 7.91 (br s, 2H), 7.87 (s, 1H), 7.82-7.78 (m, 2H), 7.45-7.38(m, 3H), 6.61 (d, 1H, J=9.3H), 5.62 9 s, 1H), 3.78 (s, 3H), 3.31-2.97(m, 4H), 2.84 (m, 6H); HRMS (FAB): Calculated for C₂₆H₂₆N₆O₂ (M+H⁺):525.1573, Found: 525.1559. Anal. calc'd for C₂₆H₂₆N₆O₂₃.0.3 Et₂O: C,59.65; H, 5.34; N, 15.35. Found C, 59.35; H, 5.25; N, 17.35.

EXAMPLE G-83-{2-[5-(6-Methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-N-(4-pyrrolidin-1-yl-3-trifluoromethylphenyl)Benzamide

[0274]

[0275] Example G-8 was made in a similar manner to that described forG-1, except that 4-(pyrrolidin-1-yl)-3-trifluoromethylaniline, preparedaccording to the procedure described in WO 99/21845 (p. 58) for thepreparation of 1-methyl-4-(4-nitrophenyl)piperazine, was used in placeof 4-isopropyl-3-methylaniline in step (d), andN-(6-methoxy-pyridin-3-yl)acetamide was used instead ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)-benzenesulfonamide, G-1b, instep (c): HPLC Rt=15.66 min; ¹H NMR (300 MHz, CDCl₃) δ 8.35 (br s, 1H),7.91 (d, 1H, J=1.5 Hz), 7.70 (d, 1H, J=1.2 Hz), 7.64 (dd, 2H, J=12.5,4.5 Hz), 7.57 (s, 1H), 7.38 (dd, 1H, J=5.3, 1.5 Hz), 7.27-7.20 (m, 1H),6.90 (d, 1H, J=5.4 Hz), 6.59 (d, 1H, J=5.1 Hz), 5.60 (s, 1H), 3.84 (s,3H), 3.25 (t, 4H, 3.6 Hz), 2.88-2.76 (m, 4H), 1.94-1.90 (m, 4H); HRMS(FAB): Calculated for C₂₉H₂₉F₃N₆O₂ (M+H⁺): 551.2382, Found: 551.2389.Anal. calc'd for C₂₉H₂₉F₃N₆O₂.0.2CH₂Cl₂: C, 61.09; H, 5.18; N, 14.59.Found C, 61.36; H, 5.18; N, 14.59.

EXAMPLE G-93-{2-[5-(6-Methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-N-[4-(4-t-butoxycarbonylpiperazin-1-yl)-3-trifluoromethylphenyl]Benzamide

[0276]

[0277] Example G-9 was made in a similar manner to that described forG-1, except that4-[4-(t-butoxycarbonyl)piperazin-1-yl]-3-trifluoromethylaniline;prepared according to the procedure described in WO 99/21845 (p. 58) forthe preparation of 1-methyl-4-(4-nitrophenyl)piperazine, was used inplace of 4-isopropyl-3-methylaniline in step (d), andN-(6-methoxy-pyridin-3-yl)acetamide was used instead ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)-benzenesulfonamide, G-1b, instep (c): ¹H NMR (300 MHz, CDCl₃) δ 8.27 (br s, 1H), 7.95-7.87 (m, 3H),7.70 (d, 1H, J=7.5 Hz), 7.59 (br s, 1H), 7.57 (s, 1H), 7.47 (dd, 1H,J=8.7, 3.0 Hz), 7.43-7.32 (m, 2H), 7.29-7.21 (m, 2H), 7.28-7.26 (m, 2H),6.66 (d, 1H, J=8.7 Hz), 5.60 (s, 1H), 3.88 (s, 3H), 3.56-3.51 (m, 4H),3.26-3.24 (m, 4H), 3.00-2.93 (m, 4H), 2.83-2.82 (m, 4H), 1.49 (s, 9H);HRMS (FAB): Calculated for C₃₄H₃₈F₃N₇O₄ (M+Na⁺): 688.2835, Found:688.2856.

[0278] Anal. calc'd for C₃₄H₃₈F₃N₇O₄.0.4H₂O: C, 60.68; H, 5.81; N,14.57. Found C, 60.90; H, 5.88; N, 14.57.

EXAMPLE G-103-{2-[5-(6-Methoxypyridin-3-yl)amino)-2H-pyrazol-3-yl]ethyl}-N-(4-piperazin-1-yl-3-trifluoromethylphenyl)Benzamide

[0279]

[0280] To a solution of 0.075 g (0.113 mmol) of3-{2-[5-(6-Methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-N-[4-(4-t-butoxycarbonyl)piperazin-1-yl-3-trifluoromethylphenyl]benzamide,G-9, in 5 mL of dichloromethane was added 5 mL of trifluoroacetic acid.After 2 h, the reaction mixture was concentrated. The residue wasdissolved in 20 mL chloroform/isopropanol (10:1) and washed with sat.aq. sodium bicarbonate (2×10 mL). The organic layer was filtered thougha silica plug using ethanol to elute product and concentrated to afford3-{2-[5-(6-methoxypyridin-3-yl)amino)-2H-pyrazol-3-yl]ethyl}-N-(4-piperazin-1-yl-3-trifluoromethylphenyl)benzamide,G-10, as off-white solid (0.056 g, 88%): HPLC Rt=12.95 min.; ¹H NMR (300MHz, CDCl₃) δ 11.38 (br s, 1H), 8.51 (br s, 1H), 7.95 (d, 1H, J=2.1 Hz),8.20-8.10 (m, 1H), 8.01 (d, 1H, J=8.7), 7.87 (s, 1H), 7.75 (d, 1H, J=6.6Hz), 7.64 (dd, 1H, J=6.5, 2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.35-7.28 (m,2H), 6.56 (d, 1H, J=8.9 Hz), 5.60 (s, 1H), 3.85 (s, 3H), 2.99-2.80 (m,12H); HRMS (FAB): Calculated for C₂₉H₃₀F₃N₇O₂ (M+H⁺): δ 566.2491, Found:566.2511.

EXAMPLE G-114-Fluoro-3-[{5-(pyridin-3-yl)amino-2H-pyrazol-3-yl}methoxy]-N-[((4-pyrrolidin-1-yl)-3-trifluoromethylphenyl)Benzamide

[0281]

[0282] Example G-11 was made in a similar manner to that described forG-1, except that 4-(pyrrolidin-1-yl)-3-trifluoromethylaniline, preparedaccording to the procedure described in WO 99/21845 (p. 58) for thepreparation of 1-methyl-4-(4-nitrophenyl)piperazine, was used in placeof 4-isopropyl-3-methylaniline in step (d), andN-(pyridin-3-yl)acetamide was used instead ofN-(diphenylmethyl)-N-methyl-4-(acetylamino)-benzenesulfonamide, G-1b, instep (c): HPLC Rt=14.78 min; ¹H NMR (300 MHz, Acetone-d₆) δ 9.53 (br s,1H), 8.55 (d, 1H, J=2.1H), 8.10 (d, 1H, J=2.7 Hz), 7.93-7.76 (m, 6H),7.45-7.37 (m, 2H), 7.20 (d, 1H, J=9.0 Hz), 7.14-7.10 (m, 1H), 3.28-3.21(m, 4H), 3.09-2.96 (m, 4H, 1.96-1.92 (m, 4H); HRMS (FAB): Calculated forC₂₈H₂₇F₃N₆O (M+H⁺): 521.2277, Found: 521.266. Anal. calc'd forC₂₈H₂₇F₃N₆O.0.9H₂O: C, 62.65; H, 5.41; N, 15.66. Found C, 62.84; H,5.33; N, 15.66.

EXAMPLE H-1N-(4-Isopropyl-3-methyl-phenyl)-3-[2-(5-phenylamino-2-H-pyrazol-3-yl)-cyclopropyl]-benzamide

[0283]

[0284] Example H-1 was made in a similar manner to that described forE-1, except thatN-(4-isopropyl-3-methylphenyl)-3-[2-(N-methoxy-N-methylcarbamoyl)cyclopropyl]benzamide,prepared as described below, was used instead of in step (c): HPLCR_(t)=16.47 min.; ¹H NMR (300 MHz, CDCl₃) δ 8.13 (br s, 1H), 7.59-7.50(m, 1H), 7.44-7.40 (m, 2H), 7.31-7.25 (m, 3H), 7.22-7.17 (m, 3H), 7.02(d, 2H, J=7.8 Hz), 6.83 (t, 1H, J=7.5 Hz), 5.71 (s, 1H), 3.14-3.53 (m,1H), 2.18-2.16 (m, 1H), 2.08-2.04 (m, 1H), 1.38-1.35 (m, 2H), 1.23 (d,6H, J=6.9 Hz); HRMS (FAB): Calculated for C₂₉H₃₀N₄O (M+H⁺): 451.2498,Found: 451.2510. Calculated for C₂₉H₃₀N₄O.0.5H₂O: C, 75.79; H, 6.80; N,12.19. Found C, 75.83; H, 6.81; N, 12.19.

[0285]N-(4-Isopropyl-3-methyl-phenyl)-3-[2-(N-methoxy-N-methyl-carbamoyl)-cyclopropyl]-benzamidewas prepared as follows: To a solution of trimethylsulfoxonium iodide(0.46 g, 2.01 mmol) in 10 mL of DMSO was added sodium hydride (0.08 g,2.01 mmol, 60% oil dispersion) at −10° C. After 30 min, to the reactionsolution was added dropwise a solution of 0.35 g (0.96 mmol) ofN-(4-isopropyl-3-methylphenyl)-3-[2-(N-methoxy-N-methylcarbamoyl)ethenyl]-benzamide,G-1e, in 5 ml of DMSO. The reaction was allowed to warm to 25° C. After2 h, the reaction was quenched with dropwise addition of 1N HCl. Thereaction mixture was partitioned between 30 mL dichloromethane and 30 mLof saturated NaHCO₃ and the organic layer was dried over sodium sulfateand evaporated to a give a crude yellow oil. The oil was purified bysilica gel chromatography using 75% hexane/25% ethyl acetate to afford0.11 g (29%) ofN-(4-isopropyl-3-methylphenyl)-3-[2-(N-methoxy-N-methylcarbamoyl)cyclopropyl]benzamideas a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 8.18 (br s, 1H), 7.67-7.62 (m,2H), 7.46-7.44 (m, 2 h), 7.36-7.26 (m, 3H), 7.20 (d, 1H, J=9.0 Hz), 3.67(s, 3H), 3.21 (S, 3H), 2.55-2.45 (m, 2H), 2.31 (s, 3H), 1.65-1.59 (m,1H), 1.37-1.31 (m, 1H), 1.21 (d, 6H, J=6.9 Hz); MS (ESI): Calculated forC₂₃H₂₈N₂O₃ (M−H): 379, Found: 379.

EXAMPLE I-13-[({3-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-5-yl}methyl)amino]-N-(3-methyl-4-isopropylphenyl)Benzamide

[0286]

[0287] (a) Vanillin (9.12 g, 0.06 mole) was dissolved in 36 mL ofacetone and 12.5 mL of 50% aq. NaOH solution was added dropwise withvigorous stirring. To the resulting solid was added 25 mL of water andthe dark red solution was refluxed for 5 min. This reaction mixture waskept at room temperature for 24 h and acidified with acetic acid. Thereaction mixture was concentrated to provide a yellow solid, which wasfiltered, washed with water and dried to yield 10.2 g (88%) of(E)-1-(3-methoxy-4-hydroxyphenyl)-1-butene-3-one, I-1a: ¹H NMR (300 MHz,CDCl₃) δ 7.43 (d, 1H, J=16.3 Hz), 7.04-7.09 (m, 2H), 6.91 (d, 1H, J=7.9Hz), 6.57 (d, 1H, J=16.3 Hz), 6.02 (s, 1H), 3.92 (s, 3H), 2.35 (s, 3H).

[0288] (b) Sodium metal (3.7 g, 0.16 mole) was dissolved in 100 mL ofabsolute ethanol under an inert atmosphere. An solution of 16.2 g (953mmol) of E-1-(3-methoxy-4-hydroxyphenyl)-1-butene-3-one, I-1a, ofethanol was then added slowly over 30 min to the sodium ethoxidesolution. After the addition the reaction mixture was stirred at for 15min followed by the addition of diethyl oxalate (7.7 g, 0.53 mole) andthe dark red solution was stirred at room temperature for 5 h.Concentrated HCl was added to the reaction mixture until acidic. A darkyellow solid separated out which was stirred in an ice bath for 1 h. Thesolid was filtered, washed and dried to afford 8.4 g (55%) of thedesired ethyl (E)-6-(4-hydroxy-3-methoxyphenyl)-2,4-dioxo-5-hexenoate,I-1b: ¹H NMR (300 MHz, CDCl₃) δ 14.86 (br s, 1H), 7.54 (d, 1H, J=15.9Hz), 7.00 (d, 1H, J=8.3 Hz), 6.93 (s, 1H), 6.81 (d, 1H, J=8.3 Hz),6.36-6.41 (m, 2H), 5.84 (s, 1H), 4.23 (q, 2H, J=7.2 Hz), 3.81 (s, 3H),1.25 (t, 3H, J=7.2 Hz).

[0289] (c) To a solution of 8.1 g (27.7 mmol) of ethyl6-(3′-methoxy-4′-hydroxyphenyl)-2,4-dioxo-5-hexenoate, I-1b, in 125 mLof acetic acid was added 1 mL of hydrazine (30.5 mmol) and the reactionwas stirred at 65° C. or 90 min. The reaction was cooled to roomtemperature and added slowly to 500 mL of ice cold water upon which awhite solid separated out. The solid was filtered, washed and dried toafford 7.25 g (91%) of ethyl(E)-3-[(2)-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazole-5-carboxylate,I-1c: ¹H NMR (300 MHz, DMSO-d₆) δ 13.61 (s, 1H), 9.34 (s, 1H), 7.23 (d,1H, J=16.6 Hz), 7.19 (s, 1H), 6.92-7.01 (m, 2H), 6.84 (d, 1H, J=7.9 Hz),4.32 (q, 2H, J=7.2 Hz) (s, 1H), 3.88 (s, 3H), 1.36 (t, 3H, J=7.2 Hz);APCIMS m/z 289 [M+H]⁺.

[0290] (d) To 40 ml of 1 M diisobutylauminum hydride in THF was addeddropwise 2.5 g (9.8 mmol) of ethyl(E)-3-[2-(3-methoxy-4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxylate,I-1c, in 25 mL of THF and the reaction was stirred at room temperature.The reaction was monitored by TLC and quenched after 6 h with water andextracted with 3×150 mL of ethyl actate. The combined organic layerswere concentrated and the residue was purified using silica gel columnchromatography to afford 1.2 g (53%) of4-{(E)-2-[5-(hydroxymethyl)-1H-pyrazol-3-yl]ethenyl}-2-methoxyphenol,I-1d: ¹H NMR (300 MHz, DMSO-d₆) δ 12.58 (br s, 1H), 9.13 (s, 1H), 7.12(s, 1H), 6.98 (d, 1H, J=16.6 Hz), 6.88-6.92 (m, 2H), 6.74 (d, 1H, J=8.4Hz), 6.34 (s, 1H), 5.10 (brs, 1H), 4.42 (d, 2H, J=5.6 Hz), 3.81 (s, 3H);APCIMS m/z 247 [M+H]⁺.

[0291] (e) To 72 mg (0.3 mmol) of4-{(E)-2-[5-(hydroxymethyl)-1H-pyrazol-3-yl]ethenyl}-2-methoxyphenol,I-1d, was added 1 mL of thionyl chloride. After 10 min, the reaction wasquenched by adding 10 mL of ice cold water slowly and the mixture wasextracted with 2×10 mL of ethyl acetate. The extracts were combined,concentrated, and filtered through a silica gel plug. All the washingswere collected, the solvent removed under vacuo to obtain 32 mg (76%) of4-{(E)-2-[5-(chloromethyl)-1H-pyrazol-3-yl]ethenyl}-2-methoxyphenol,I-1e: ¹H NMR (300 MHz, DMSO-d₆) δ 12.89 (brs, 1H), 9.20 (s, 1H), 7.11(s, 1H), 7.04 (d, 1H, J=16.7 Hz), 6.74-6.90 (m, 2H), 6.75 (d, 1H, J=8.0Hz), 6.45 (s, 1H), 4.69 (s, 2H), 3.81 (s, 3H); APCIMS m/z 265 [M+H]⁺.

[0292] (f) To 132 mg (0.5 mmol) of4-{(E)-2-[5-(chloromethyl)-1H-pyrazol-3-yl]ethenyl}-2-methoxyphenol,I-1e, in 2 mL of DMF was added 3-aminobenzoic acid (75 mg, 0.55 mmol)and an excess of NaHCO₃ and the reaction mixture stirred at roomtemperature for 16 h. The crude reaction mixture was filtered through aplug of silica gel to remove NaHCO₃ and washed with ethyl acetate. Thefiltrates were collected and the solvents removed in vacuo to yield 60mg of crude3-[({3-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-5-yl}methyl)amino]benzoicacid, I-1f, which was redissolved in 2 mL of DMF. To the resultingsolution were added HATU (95 mg, 0.25 mmol) and diisopropylethylamine(0.04 mL, 0.23 mmol) followed by 3-methyl-4-isopropylaniline (90 mg, 0.6mmol) and the reaction mixture stirred at room temperature for 16 h.After conventional aqueous work-up, 16 mg of3-[({3-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-5-yl}methyl)amino]-N-(3-methyl-4-isopropylphenyl)benzamide,I-1, was isolated using HPLC; ¹H NMR (300 MHz, DMSO-d₆) δ 9.91 (s, 1H),7.51-7.54 (m, 2H), 7.03-7.20 (m, 7H), 6.98 (d, 1H, J=15.5 Hz), 6.82-6.90(m, 4H), 6.74 (d, 1H, J=9.0 Hz), 6.35 (s, 1H), 4.28 (s, 2H), 3.80 (s,3H), 3.01-3.08 (m, 1H), 2.27 (s, 3H), 1.16 (d, 6H, J=6.0 Hz); APCIMS m/z497 [M+H]⁺.

EXAMPLE I-23-[({5-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-3-yl}methyl)amino]-N-phenylbenzamide

[0293]

[0294] Example I-2 was prepared in a similar manner to that describedfor I-1, except that aniline was used in place of3-methyl-4-isopropylaniline in step (f): HPLC R_(t)=6.38 min.; ¹H NMR(300 MHz, CD₃OD) δ 7.55 (d, 2H, J=9.0 Hz), 7.21-7.26 (m, 2H), 7.11-7.16(m, 2H), 7.02-7.08 (m, 2H), 6.97-6.98 (m, 1H), 6.90 (d, 1H, J=15.0 Hz),6.78-6.86 (m, 2H), 6.74 (d, 1H, J=15.0 Hz), 6.65-6.67 (m, 1H), 6.33 (s,1H), 4.27 (s, 2H), 3.77 (s, 3H); APCIMS m/z 441 [M+H]⁺.

EXAMPLE J-14-Fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-3-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-ylmethoxy]-benzamide

[0295]

[0296] (a) To a solution of 2-bromo-5-nitrobenzotrifluoride (1.50 g,5.54 mmol) in toluene (11 mL) under argon purge was added imidazole(0.57 g, 8.31 mmol), trans,trans-dibenzylidene acetone (0.13 g, 0.56mmol), 1,10-phenanthroline (1.00 g, 5.54 mmol), cesium carbonate (1.99g, 6.10 mmol) and copper(II)triflate•benzene (0.015 g, 0.028 mmol). Theslurry was heated at 90° ° C. for 18 h, and then cooled to 25° C. Themixture was filtered through a silica gel plug with 30 mL of ethylacetate and the filtrate was concentrated. The residue was purified bychromatography on silica gel (hexane/ethyl acetate) to afford 0.83 g(58.2%) of 1-(4-Nitro-2trifluoromethylphenyl)-1H-imidazole, J-1a, as anamber solid: HPLC Rt=10.45 min.; ¹H NMR (300 MHz, CDCl₃) δ 8.72 (d, 1H,J=2.1 Hz), 8.58 (dd, 1H, J=8.7, 2.7 Hz), 7.70-7.67 (m, 2H), 7.26 (s,1H), 7.21 (s, 1H); MS (ESI): Calculated for C₁₀H₆F₃N₃O₂ (M+H⁺): 257,Found: 257.

[0297] (b) To a solution of 0.60 g (2.33 mmol) of1-(4-nitro-2-trifluoromethylphenyl)-1H-imidazole, J-1a, in 10 mL ofmethanol was added 0.10 g of 10% Pd/C. The mixture was stirred under ahydrogen atmosphere (1 atm) for 18 h, and then filtered through a 0.22μM teflon filter membrane. The filtrate was concentrated to afford 0.51g (100%) of 1-(4-amino-2-trifluomethylphenyl)imidazole, J-1b, as ayellow solid: HPLC Rt=8.89 min.; ¹H NMR (300 MHz, CDCl₃) δ 7.62 (s, 1H),7.13-7.02 (m, 4H), 6.86 (d, 1H, J=8.4, 2.4 Hz). MS (ESI): Calculated forC₁₀H₈F₃N₃ (M+H⁺): 228, Found: 228.

[0298] (c) To a solution of 3-acetoxy-4-fluorobenzoic acid (0.49 g, 2.48mmol) in dichloromethane (5 mL) was added oxayl chloride (0.26 ml, 2.97mmol) and DMF (0.1 mL). After 1 h, the mixture was concentrated and thenre-dissolved in 5 mL of dichloromethane. To this solution was added 0.56g (2.47 mmol) of 1-(4-amino-2-trifluomethylphenyl)imidazole, J-1b, anddiisopropylethylamine (0.39 mL, 2.48 mmol). After 1 h the solution waspartitioned between 30 mL of ethyl acetate and sat. aq. sodiumbicarbonate (2×20 mL). The organic layer was dried over sodium sulfateand concentrated. The residue was purified by chromatography on silicagel (1:1 hexane:ethyl acetate) to provide 0.49 g (57%) of3-acetoxy-4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-benzamide,J-1c, as clear oil: ¹H NMR (300 MHz, CDCl₃) δ 8.12-8.02 (m, 3H),7.92-7.89 (m, 1H), 7.63 (s, 1H), 7.37-7.12 (m, 5H), 2.36 (s, 1H); MS(ESI): Calculated for C₁₉H₁₃F₄N₃O₃ (M+H⁺): 408, Found: 408.

[0299] (d) To a solution of 0.33 g (0.83 mmol)3-acetoxy-4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-benzamide,J-1c, in 5 mL acetone and 0.5 mL of methanol was added cesium carbonate(0.54 g, 1.65 mmol) and 2-chloro-N-methoxy-N-methyl-acetamide (0.15 g,1.07 mmol) and the resulting mixture was stirred for 6 h at 45° C. Aftercooling to room temperature, the mixture was partitioned between ethylacetate and sat. brine (2×20 mL). The organic layer was filtered thougha silica gel plug and concentrated. The residue was purified bytiturated with diethyl ether (2×20 mL) to give 0.35 g (92%) of4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-3-[(N-methoxy-N-methylcarbamoyl)methoxy]benzamide,J-1d, as a white solid: Rt=11.95 min.; ¹H NMR (300 MHz, CDCl₃) δ 8.34(d, 1H, J=2.4 Hz), 8.11 (dd, 1 h, J=8.7 Hz), 7.64-7.54 (m, 3H), 7.42 (d,1H, J=8.7 Hz), 7.22-7.15 (m, 2H), 6.97 (s, 1H), 502 (s, 2H), 3.72 (s,3H), 3.06 (s, 3H); MS (ESI): Calculated for C₂₁H₁₈F₄N₄O₄ (M+H⁺): 467,Found: 467.

[0300] (e) To a −78° C. solution of 0.13 g (0.71 mmol)N-(6-methoxy-pyridin-3-yl)-thioacetamide in 5 mL of dry THF was addeddropwise 0.71 mL (1.42 mmol) of LDA (2.0 M in THF). The solution wasstirred for 15 min at −78° C., warmed to 0° C. for 1 h, and then cooledto −78° C. To the resulting solution was added, over a 5 min period, asolution of 0.15 g (0.32 mmol)4fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethyl-phenyl]-3-[(N-methoxy-N-methylcarbamoyl)methoxy]benzamide,J-1d, in 5 mL of THF. After stirring for 1 h at 0° C., the reaction wasquenched with 1 mL of 1:1 methanol:acetic acid. The mixture waspartitioned between ethyl acetate and sat. sodium carbonate (2×20 mL)and the organic layer was dried over sodium sulfate and concentrated.The residual yellow oil was purified by radial chromatography (2 mmplate eluting with 1:2:1 hexane:ethyl acetate:dichloromethane) to give0.091 g (49%) of4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-3-[3-(6-methoxypyridin-3-yl)thiocarbamoyl-2-oxo-propoxy]-benzamide,J-1e, as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.74 (br s, 1H), 8.19(d, 2H, J=2.7 Hz), 8.05 (d, 1H, J=2.7 Hz), 7.96 (dd, 2H, J=10.2, 3.0Hz), 7.41 (dd, 1H, J=8.4, 2.7 Hz), 7.28 (s, 1H), 6.82-6.77 (m, 4H), 2.74(s, 2H); MS (ESI): Calculated for C₂₇H₂₁F₄N₅O₄S (M+H⁺): 588, Found: 588.

[0301] (e) To a solution of 0.061 g (0.10 mmol) of4-fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethyl-phenyl]-3-[3-(6-methoxypyridin-3-yl)thiocarbamoyl-2-oxo-propoxy]-benzamide,J-1e, in ethanol (2 mL) was added hydrazine monohydrate (0.080 mL, 0.16mmol) and acetic acid (0.09 mL, 0.16 mmol). After 2 h the solution wasconcentrated and the residue was purified by chromatography on silicagel (1:2 hexane:ethyl acetate) to afford 0.031 g (54%) of4-fluoro-N-(4-(imidazol-1-yl)-3-trifluoromethyl-phenyl)-3-[5-(6-methoxy-pyridin-3-yl)amino-2H-pyrazol-3-ylmethoxy]benzamide,J-1, as a off white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.34 (s, 1H),8.12-8.10 (m, 2H), 7.85 (t, 1H, 3.0 Hz), 7.69-7.57 (m, 2H), 7.41 (d, 1H,J=8.7 Hz), 7.22-7.13 (m, 2H), 6.97 (d, 1H, J=6.0 Hz), 6.52 (d, 1H, J=9.0Hz), 5.88 (s, 1H), 5.19 (s, 2H), 3.68 (s, 3H); LCESI: Calculated forC₂₇H₂₁F₄N₇O₃ (M+H⁺): 568, Found: 568. Anal. calc'd forC₂₇H₂₁F₄N₇O₃.1.2CH₂Cl₂ Found: C, 50.59; H 3.52; N, 14.65. Found C,50.69; H, 3.78; N, 14.79.

EXAMPLE J-24-Fluoro-3-[5-(6-methoxy-pyridin-3-yl)amino-2H-pyrazol-3-yl]methoxy-N-(4-pyrrolidin-1-yl-3-trifluoromethyl-phenyl)-benzamide

[0302]

[0303] Example J-2, was prepared in a similar manner to that describedfor J-1, except that 4-(pyrrolidino)-3-trifluoromethylaniline (seeexample G-8) was used in place of1-(4-amino-2-trifluomethylphenyl)imidazole, J-1b, in step (c): HPLCRt=15.55 min.; ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, 1H, J=2.7 Hz), 7.85(br s, 1H), 7.68-7.63 (m, 3H), 7.49 (dd, 1H, J=8.7, 3.0 Hz), 7.18-7.11(m, 1H), 6.95 (d, 1H, J=8.7 Hz), 6.67 (d, 1H, J=8.7 Hz), 5.93 (s, 1H),5.87 (s, 1H), 5.17 (s, 2H), 3.88 (s, 3H), 3.31-3.27 (m, 4H), 2.05-1.96(m, 4H); HRMS (MALDI): Anal. Calculated for C₂₈H₂₆F₄N₆O₃ (M+Na⁺):593.1900, Found: 593.1873. Anal. calc'd for C₂₈H₂₆F₄N₆O₃ C, 58.95; H,4.95; N, 14.73. Found C, 58.87; H, 4.91; N, 14.87.

EXAMPLE J-34-Fluoro-3-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]methoxy-N-(3-methoxy-5-trifluoromethyl-phenyl)-benzamide

[0304]

[0305] Example J-3, was prepared in a similar manner to that describedfor J-1, except that 5-methoxy-3-trifluoromethylaniline (Aldrich) wasused in place of 1-(4-amino-2-trifluomethylphenyl)imidazole, J-1b, instep (c): Rt=14.50 min.; ¹H NMR (300 MHz, CDCl₃) δ 8.05 (d, 1H, J=3.0Hz), 7.88 (s, 1H), 7.68 (dd, 1H, J=9.5, 2.1 Hz), 7.56-7.53 (m, 2H),7.42-7.39 (m, 1H), 7.34 (s, 1H), 7.26-7.17 (m, 1H), 6.94 (s, 1H), 7.70(d, 1H, J=9.0 Hz), 5.95 (s, 1H), 5.76 (br s, 1H), 5.21 (s, 2H), 3.90 (s,3H), 3.87 (s, 3H); HRMS (FAB): Calculated for C₂₅H₂₁F₄N₅O₄ (M+Na⁺):554.1427, Found: 554.1423. Anal. calc'd for C₂₅H₂₁F₄N₅O₄.0.2hexane: C,57.35; H, 4.37; N, 12.76. Found C, 57.00; H, 4.60; N, 13.00.

EXAMPLE K-1N-(4-Isopropyl-3-methyl-phenyl)-3-(Isoquinolin-4-yl)methoxy-benzamide

[0306]

[0307] (a) A 2.6 M solution of n-BuLi in hexanes (7.4 mL, 19.2 mmol, 2.0eq) was added to a solution of THF (40 mL) and ether (40 mL) and cooledto −78° C. 4-Bromoisoquinoline (Aldrich, 2.0 g, 9.6 mmol, 1.0 eq) wasadded to the anion in one portion and the dark orange solution was agedat −78° C. for 30 minutes to give a brown slurry. The mixture wastreated with DMF (1.7 mL, 24.0 mmol, 2.5 eq) to give a brown solution.After 15 min, the reaction was quenched with ethanol (40 mL). Theresultant pale yellow solution was treated with a saturated solution ofammonium chloride (200 mL) and extracted with MTBE (3×200 mL). Thecombined organic extracts were washed with brine (200 mL), dried overmagnesium sulfate, filtered and concentrated under reduced pressure togive an orange solid (1.8 g). The crude product was purified by flashchromatography over silica gel using 50% ethyl acetate/cyclohexane(R_(f) 0.5) to give isoquinoline-4-carbaldehyde, K-1a, as a yellow solid(1.3 g, 84%): HPLC R_(t)=8.8 min.; TLC R_(f)=0.2 (5% ethyl acetate/35%cyclohexane/dichloromethane); ¹H NMR (300 MHz, CDCl₃) δ 10.41 (s, 1H),9.46 (s, 1H), 9.23 (d, 1H, J=8.5 Hz), 8.95 (s, 1H), 8.12 (d, 1H, J=8.1Hz), 7.97 (t, 1H, J=7.6 Hz), 7.78 (t, 1H, J=7.3 Hz); MS (ESI) m/z 158[M+H]⁺.

[0308] (b) To a solution of 1.4 g (8.9 mmol) ofisoquinoline-4-carbaldehyde, K-1a, in ethanol (50 mL) at 0° C. was addedwith sodium borohydride (372 mg, 9.8 mmol, 1.1 eq). The mixture wasstirred at 0° C. for 1.5 hours and at room temperature for 1.0 h. Thereaction was quenched with 25% ammonium acetate (500 mL). The ethanolwas removed under reduced pressure and the resultant mixture wasextracted with ethyl acetate (3×500 mL). The combined organic extractswere washed with brine (200 mL), dried over magnesium sulfate, filteredand concentrated under reduced pressure to give a yellow oil (1.5 g).The crude product was purified by radial chromatography over silica gelusing 5-10% methanol/dichloromethane to give, after concentration from50% ethyl acetate/cyclohexane, 4-(hydroxymethyl)isoquinoline, K-1b, as atan solid (0.95 g, 68%): HPLC R_(t)=6.7 min.; TLC R_(f)=0.2 (50% ethylacetate/cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.49 (s,1H), 8.14 (d, 1H, J=8.4 Hz), 7.82 (t, 1H, J=7.6 Hz), 7.70 (t, 1H, J=7.6Hz), 5.36 (t, 1H, J=5.4 Hz), 4.95 (d, 2H, J=5.2 Hz); MS (FAB) m/z 160[M+H]⁺.

[0309] (c) A solution of 4-(hydroxymethyl)isoquinoline, K-1b, (900 mg,5.7 mmol, 1.0 eq) in ethanol (10 mL) was treated with concentratedhydrochloric acid (1.0 mL, 12.6 mmol, 2.1 eq). The mixture was stirredfor 30 min and then the solvent was removed under reduced pressure. Thetan residue was repeatedly evaporated from toluene (3×10 mL) to give atan solid (1.1 g, 100%). The resulting unpurified4-(hydroxymethyl)isoquinoline hydrochloride was then treated withthionyl chloride (10 mL) and the resultant mixture was heated to 70° C.After 1.5 hours, the solvent was removed under reduced pressure to give4-(chloromethyl)isoquinoline hydrochloride, K-1c, as a tan solid (1.1 g,95%): HPLC R_(t)=11.2 min.; ¹H NMR (300 MHz, DMSO-d₆) δ 9.81 (s, 1H),8.83 (s, 1H), 8.52 (d, 1H, J=8.1 Hz), 8.42 (d, 1H, J=8.6 Hz), 8.23 (t,1H, J=7.8 Hz), 8.01 (t, 1H, J=7.8 Hz), 5.41 (s, 2H); ¹³C NMR (75 MHz,DMSO-d₆) δ 149.6, 136.2, 135.9, 134.1, 131.9, 131.4, 130.6, 127.8,124.2; MS (FAB) m/z 177/179 [M⁻]. Anal. calc'd for C₁₀H,ClN.HCl: C,56.10; H, 4.24; Cl, 33.12; N, 6.54. Found: C, 56.15; H, 4.32; Cl, 33.23;N, 6.37.

[0310] (d) A suspension of 3-methyl-4-isopropyl aniline hydrochloride(6.7 g, 36.2 mmol, 1.0 eq) in THF (240 mL) was treated withtriethylamine (5.0 mL, 36.2 mmol, 1.0 eq). The gray mixture was thentreated with 3-hydroxybenzoic acid (Aldrich, 5.0 g, 36.2 mmol, 1.0 eq),followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(7.6 g, 39.8 mmol, 1.1 eq). The resultant slurry was stirred at roomtemperature for 18 h. The solvent was removed under reduced pressure andthe residue was extracted with water (200 mL) and ethyl acetate (3×200mL). The combined organic extracts were washed with 5% KHSO₄ (2×200 mL),water, (200 mL), brine (200 mL), dried over magnesium sulfate, filteredand concentrated under reduced pressure to give a brown solid (8.0 g).The crude product was purified by flash chromatography on silica gelusing 3-5% methanol/dichloromethane to give3-hydroxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide, K-1d, as anoff-white solid (1.1 g, 11%): HPLC R^(t)=13.9 min.; TLC R_(f)=0.4 (3%methanol/dichloromethane); ¹H NMR (500 MHz, DMSO-d₆) δ 9.99 (s, 1H),9.71 (s, 1H), 7.55-7.29 (m, 5H), 7.19 (d, 1H, J=8.1 Hz), 7.97-7.95 (m,1H), 3.09-3.06 (m, 1H), 2.29 (s, 3H), 1.18 (d, 6H, J=6.9 Hz); ¹³C NMR(75 MHz, DMSO-d₆) δ 165.6, 157.7, 142.0, 136.9, 134.9, 129.7, 125.0,122.4, 118.8, 118.7, 118.4, 114.8, 28.7, 23.5, 19.5; MS (ESI) m/z 268[M−H]⁻. Anal. calc'd for C₁₇H₁₉NO₂: C, 75.81; H, 7.11; N, 5.20. Found:C, 75.35; H, 7.23; N, 5.12.

[0311] (e) To a clear solution of3-hydroxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide, K-1d, (0.538 g, 2.0mmol, 1.0 eq) in acetone (40 mL) was added cesium carbonate (5.2 g, 16.0mmol, 8.0 eq). The resultant mixture was stirred at room temperature for30 minutes, treated with 4-chloromethyl-isoquinoline hydrochloride,K-1c, (0.469 g, 2.2 mmol, 1.1 eq) and warmed to 50° C. After 18 hours,the reaction was diluted with water (200 mL) and extracted with ethylacetate (3×200 mL). The combined organic extracts were washed with brine(300 mL), dried over magnesium sulfate, filtered and concentrated underreduced pressure to give a yellow oil (1.7 g). The oil was purified byradial chromatography over silica gel eluting with 50% ethylacetate/cyclohexane (R_(f) 0.3) to give, after concentration from MTBE,N-(4-isopropyl-3-methyl-phenyl)-3-(Isoquinolin-4-yl)methoxy-benzamide,K-1, (0.69 g, 83%) as a light yellow foam: HPLC R_(t)=16.9 min.; TLCR_(f)=0.6 (3% methanol/chloroform); ¹H NMR (500 MHz, DMSO-d₆) δ 10.06(s, 1H), 9.37 (s, 1H), 8.69 (s, 1H), 8.22 (d, 1H, J=8.1 Hz), 8.17 (d,1H, J=8.5 Hz), 7.90 (t, 1H1J=7.7 Hz), 7.77 (t, 1H, J=7.5 Hz), 7.69 (s,1H), 7.60-7.34 (m, 5H), 7.21 (d, 1H, J=8.4 Hz), 5.66 (s, 2H), 3.09-3.07(m, 1H), 2.30 (s, 3H), 1.18 (d, 6H, J=6.8 Hz); ¹³C NMR (75 MHz, DMSO-d₆)δ 165.1, 158.6, 153.9, 143.5, 142.2, 136.8, 136.7, 135.0, 134.1, 131.5,130.0, 128.6, 128.3, 128.0, 126.0, 125.0, 123.6, 122.5, 120.7, 118.8,118.3, 114.3, 66.2, 28.7, 23.5, 19.4; MS (ESI) m/z 411 [M+H]⁺. Anal.calc'd for C₂₇H₂₆N₂O₂.0.3H120: C, 77.97; H, 6.45; N, 6.74. Found: C,77.76; H, 6.64; N, 6.48.

EXAMPLE K-23-(Isoquinolin-4-yl)methoxy-N-(3,4,5-trimethoxyphenyl)BenzamideHydrochloride

[0312]

[0313] Example K-2 was prepared in a similar manner to that describedfor K-1, except that 3,4,5-trimethoxyaniline (Aldrich) was used in placeof 3-methyl-4-isopropylaniline in step (d). The product was isolated asthe hydrochloride salt as follows. A solution of3-(isoquinolin-4-yl)methoxy-N-(3,4,5-trimethoxyphenyl)benzamide (116 mg,0.26 mmol) in ethanol was treated with concentrated hydrochloric acid(0.1 mL, 1.2 mmol). After several minutes, the solvent was removed underreduced pressure to give3-(isoquinolin-4-yl)methoxy-N-(3,4,5-trimethoxyphenyl)benzamidehydrochloride as a white solid (126 mg, 100%): HPLC R_(t)=13.4 min.; TLCR_(f)=0.5 (5% methanol/chloroform); ¹H NMR (300 MHz, DMSO-d₆) δ 10.10(s, 1H), 9.70 (s, 1H), 8.72 (s, 1H), 8.41 (d, 1H, J=8.1 Hz), 8.30 (d,1H, J=8.5 Hz), 8.10 (t, 1H, J=7.8 Hz), 7.90 (t, 1H, J=7.6 Hz), 7.67 (s,1H), 7.53 (d, 1H, J=7.7 Hz), 7.41 (t, 1H, J=7.9 Hz), 7.29 (dd, 1H,J=8.2, 1.6 Hz), 7.16 (s, 2H), 5.70 (s, 2H), 3.66 (s, 6H), 3.53 (s, 3H);¹³ C NMR (75 MHz, DMSO-d₆) δ 165.1, 158.2, 152.9, 149.5, 136.7, 136.1,135.8, 135.6, 134.2, 133.5, 131.0, 130.9, 130.3, 130.0, 127.6, 124.4,121.0, 118.6, 114.5, 98.6, 65.4, 60.5, 56.1; MS (ESI) m/z 445 [M+H]⁺.Anal. calc'd for C₂₅H₂₂N₄O₃.HCl.0.5H₂O: C, 63.73; H, 5.35; N, 5.72.Found: C, 63.52; H, 5.51; N, 5.50.

EXAMPLE K-33-(Isoquinolin-4-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamideHydrochloride

[0314]

[0315] Example K-3, which was isolated as a dihydrochloride salt asdescribed in Example K-2, was prepared in a similar manner to thatdescribed for K-1, except that 6-amino-2-methylquinoline (Maybridge) wasused in place of 3-methyl-4-isopropylaniline in step (d): HPLCR_(t)=13.2 min.; TLC R_(f)=0.5 (5% methanol/chloroform); ¹H NMR (300MHz, DMSO-d₆ w/ D₂O) δ 9.78 (s, 1H), 9.0 (d, 1H, J=8.7 Hz), 8.84 (d, 2H,J=1.9 Hz), 8.55 (d, 1H, J=8.2 Hz), 8.45-8.40 (m, 2H) 8.27-8.22 (m, 2H),8.05 (t, 1H, J=7.5 Hz), 7.92 (d, 1H, J=8.7 Hz), 7.83 (t, 1H, J=1.8 Hz),7.72 (d, 1H, J=7.7 Hz), 7.60 (t, 1H, J=8.0 Hz), 7.48 (dd, 1H, J=8.2, 1.8Hz), 5.84 (s, 2H), 2.95 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆ w/ D₂O) δ167.9, 159.8, 158.2, 151.2, 146.7, 140.7, 137.6, 137.4, 136.3, 135.4,132.6, 132.2, 132.1, 132.0, 130.3, 129.2, 129.1, 125.9, 125.7, 122.9,122.7, 120.8, 118.7, 116.1, 66.9, 22.0; MS (FAB) m/z 420 [M+H]⁺. Anal.calc'd for C₂₇H₂₁N₃O₂.2HCl. 0.3H₂O: C, 65.14; H, 4.78; N, 8.44. Found:C, 65.18; H, 4.84; N, 8.38.

EXAMPLE K-43-(Isoquinolin-4-yl)methoxy-N-(2-methyl-4-methylsulfanyl-quinolin-6-yl)-benzamideHydrochloride

[0316]

[0317] Example K-4, which was isolated as a dihydrochloride salt asdescribed in Example K-2, was prepared in a similar manner to thatdescribed for K-1, except that2-methyl-4-methylsulfanyl-quinolin-6-ylamine, K-4d (vide infra), wasused in place of 3-methyl-4-isopropylaniline in step (d): HPLCR_(t)=14.4 min.; TLC R_(f)=0.5 (5% methanol/chloroform); ¹H NMR (500MHz, DMSO-d₆) δ 11.10 (s, 1H), 9.80 (s, 1H), 9.07 (s, 1H), 8.89 (s, 1H),8.54 (t, 2H, J=7.6 Hz), 8.46 (d, 1H, J=8.5 Hz), 8.33 (d, 1H, J=9.2 Hz),8.22 (t, 1H, J=7.5 Hz), 8.04 (t, 2H, J=7.6 Hz), 7.95 (s, 1H), 7.79-7.78(m, 2H), 7.63 (t, 1H, J=7.9 Hz), 7.52 (d, 1H, J=6.6 Hz), 5.88 (s, 2H),2.94 (s, 3H), 2.92 (s, 3H); HRMS (FAB) calcd for C₂₈H₂₃N₃O₂S [M+H]⁺466.1589, found 466.1577.

[0318] The intermediate 2-methyl-4-methylsulfanyl-quinolin-6-ylamine,K-4d, was prepared as follows:

[0319] (a) A solution of 2-methyl-quinolin-4-ol (Aldrich, 9.2 g, 57.9mmol. 1.0 eq) in concentrated sulfuric acid (60 mL) was cooled to 0° C.and treated with fuming nitric acid (3.9 mL, 57.9 mmol, 1.0 eq). Thedark orange solution was stirred at 0° C. for 15 minutes and then pouredinto ice water (1000 mL) to give a yellow precipitate. After standingfor 18 hours, the mixture was filtered and the yellow precipitate waswashed with ice water to give 2-methyl-6-nitro-quinolin-4-ol, K-4a, as ayellow solid (6.9 g, 58%): HPLC R_(t)=6.8 min.; ¹H NMR (500 MHz,DMSO-d₆) δ 8.10 (s, 1H), 8.42 (dd, 1H, J=9.2, 2.6 Hz), 7.70 (d, 1H,J=9.1 Hz), 6.15 (s, 1H), 2.42 (s, 3H); MS (ESI) m/z 203 [M−H]⁻.

[0320] (b) A solution of 2-methyl-6-nitro-quinolin-4-ol, K-4a, (6.9 g,33.8 mmol) in phosphorus oxychloride (70 mL) was heated to 95° C. After1 hour, the reaction mixture gives no starting material by HPLCanalysis. The black solution was cooled to room temperature and pouredinto ice water (500 mL). The aqueous layer was made basic by theaddition of concentrated ammonium hydroxide, and extracted withchloroform (3×500 mL). The combined organic extracts were washed with5.0 N ammonium hydroxide (500 mL), water (500 mL), brine (500 mL), driedover magnesium sulfate, filtered and concentrated under reducedpressure. The crude product was passed through a silica gel plug,eluting with 20% ethyl acetate/chloroform, to give a brown solid (6.4g). The product was crystallized from hot ethanol to give4-chloro-2-methyl-6-nitro-quinoline, K-4b, as tan needles (3.6 g, 48%):mp 142-144° C.; HPLC R_(t)=13.5 min.; TLC R_(f)=0.3 (20% ethylacetate/cyclohexane); ¹H NMR (500 MHz, DMSO-d₆) δ 8.92, (d, 1H, J=2.5Hz), 8.52 (dd, 1H, J=9.2, 2.6 Hz), 8.20 (d, 1H, J=9.2 Hz), 7.94 (s, 1H),2.73 (s, 3H); MS (ESI) m/z 223 [M+H]⁺.

[0321] (c) A solution of 4-chloro-2-methyl-6-nitro-quinoline, K-4b, (372mg, 1.7 mmol, 1.0 eq) in anhydrous ethanol (70 mL) was treated withsodium thiomethoxide (619 mg, 8.8 mmol, 5.2 eq), and the resultant greenslurry was heated at 50° C. After 2.5 hours, the solvent was removedunder reduced pressure and the residue was partitioned between water(100 mL) and chloroflorm,(3×100 mL). The combined organic extracts werewashed with brine (100 mL), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give a yellow solid (430 mg). Thecrude product was purified by radial chromatography over silica gelusing 5% ethyl acetate/chloroform, followed by crystallization from hotethanol, to give 2-methyl-4-methylsulfanyl-6-nitro-quinoline, K-4c, asyellow needles (250 mg, 46%): HPLC R_(t)=13.1 min.; TLC R_(f)=0.5 (10%ethyl acetate/chloroform); ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (d, 1H,J=2.4 Hz), 8.32 (dd, 1H, J=9.2, 2.5 Hz), 7.97 (d, 1H, J=9.2 Hz), 7.35(s, 1H), 2.61 (s, 3H), 2.58 (s, 3H); MS (ESI) m/z 235 [M+H]⁺.

[0322] (d) A mixture of 2-methyl-4-methylsulfanyl-6-nitro-quinoline,K-4c, (200 mg, 0.85 mmol, 1.0 eq), and tin(II) chloride dihydrate (965mg, 4.27 mmol, 5.0 eq) in anhydrous ethanol (50 mL) was heated to 75° C.to give an orange solution. After 30 minutes, the reaction mixture wasconcentrated under reduced pressure to about 10 mL. The resultantmixture was poured into ice water (100 mL), and the aqueous layer wasadjusted to pH 10 using concentrated ammonium hydroxide. The aqueouslayer was extracted with ethyl acetate (3×100 mL), the combined organiclayers were washed with brine (100 mL), dried over magnesium sulfate,filtered and concentrated under reduced pressure to give a yellow solid(250 mg). The crude product was purified by radial chromatography oversilica gel using 30% ethyl acetate/dichloromethane w/ 0.5% methanol togive 2-methyl-4-methylsulfanyl-quinolin-6-ylamine, K-4d, as a yellowsolid (70 mg, 40%): HPLC R_(t)=9.0 min.; TLC R_(f)=0.6 (5%methanol/chloroform); ¹H NMR (500 MHz, DMSO-d₆) δ 7.58 (d, 1H, J=8.9Hz), 7.08 (dd, 1H, J=8.9, 2.4 Hz), 7.02 (s, 1H), 6.90 (d, 1H, J=2.4 Hz),5.58 (s, 2H), 2.58 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z 205 [M+H]⁺.

EXAMPLE K-5 3-(Pyridin-3-yl)methoxy-N-(3,4,5-trimethoxyphenyl)Benzamide

[0323]

[0324] Example K-5, which was obtained as a white solid in a 62% yield,was prepared in a similar manner to that described for K-1, except that3,4,5-trimethoxyaniline was used in place of 3-methyl-4-isopropylanilinein step (d), and 3-picolyl chloride hydrochloride was used in place of4-(chloromethyl)isoquinoline hydrochloride, K-1c, in step (e): HPLCR_(t)=18.1 min.; TLC R_(f)=0.5 (5% methanol/chloroform); ¹H NMR (500MHz, CDCl₃) δ 8.73 (s, 1H), 8.60 (d, 1H, J=2.9 Hz), 8.22 (s, 1H), 7.91(d, 1H, J=7.4 Hz), 7.61 (s, 1H), 7.52-7.41 (m, 3H), 7.16 (d, 1H, J=7.6Hz), 7.04 (s, 2H), 5.19 (s, 2H), 3.87 (s, 6H), 3.85 (s, 3H); ¹³C NMR(125 MHz, CDCl₃) δ 165.2, 158.5, 153.3, 147.9, 147.4, 136.6, 136.4,134.9, 134.0, 133.0, 130.0, 124.0, 119.7, 118.8, 113.3, 98.0, 67.4,61.0, 56.1; MS (FAB) m/z 395 [M+H]⁺. Anal. calc'd for C₂₂H₂₂N₂O₅: C,66.99; H, 5.62; N, 7.10. Found: C, 67.00; H, 5.65; N, 7.09.

EXAMPLE K-6 N-(Naphthalen-2-yl)-3-(pyridin-3-yl)Methoxybenzamide

[0325]

[0326] Example K-6, which was obtained as a white solid in a 19% yield,was prepared in a similar manner to that described for K-1, except2-aminonaphthalene (Aldrich) was used in place of3-methyl-4-isopropylaniline in step (d), and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, in step (e): HPLC R_(t)=22.5 min.; TLC R_(f)=0.4(5% methanol/chloroform); ¹H NMR (300 MHz, CDCl₃) δ 10.41 (s, 1H), 8.72(d, 1H, J=1.8 Hz), 8.58 (dd, 1H, J=4.8, 1.6 Hz), 8.44 (d, 1H, J=1.5 Hz),7.94-7.81 (m, 5H), 7.68-7.62 (m, 2H), 7.53-5.28 (m, 5H), 5.27 (s, 2H);¹³C NMR (125 MHz, DMSO-d₆) δ 165.6, 158.5, 149.6, 149.5, 137.0, 136.7,136.1, 133.7, 132.8, 130.4, 130.0, 128.5, 127.8, 127.7, 126.7, 125.2,124.0, 121.3, 120.7, 118.4, 117.0, 114.4, 67.6; MS (FAB) m/z 355 [M+H]⁺.Anal. calcd for C₂₃H₁₈N₂O₂: C, 77.95; H, 5.12; N, 7.70. Found: C, 77.41;H, 5.22; N, 7.79.

EXAMPLE K-7 N-(1-Allyl-1H-indol-5-yl)-3-(pyridin-3-yl)methoxy-benzamide

[0327]

[0328] Example K-7, which was obtained as a light yellow solid in a 25%yield, was prepared in a similar manner to that described for K-1,except 1-allyl-1H-indol-5-ylamine, K-7b (vide infra), was used in placeof 3-methyl-4-isopropylaniline in step (d), and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, in step (e): HPLC R_(t)=21.6 min.; TLC R_(f)=0.7(5% methanol/chloroform); ¹H NMR (300 MHz, DMSO-d₆) δ 10.14 (s, 1H),8.77 (d, 1H, J=1.5 Hz), 8.62 (d, 1H, J=5.1 Hz), 8.05 (s, 1H), 7.98 (d,1H, J=8.1 Hz), 7.68-7.66 (m, 2H), 7.53-7.28 (m, 7H), 6.49 (d, 1H, J=2.9Hz), 6.10-6.01 (m, 1H), 5.30 (s, 2H), 5.20 (d, 1H, J=10.3 Hz), 5.05 (d,1H, J=17.3 Hz), 4.86 (d, 2H, J=5.2 Hz); HRMS (FAB) calcd for C₂₄H₂₁N₃O₂[M+H]⁺ 384.1712, found 384.1708. The intermediate1-allyl-1H-indol-5-ylamine, K-7b, was prepared as follows:

[0329] (a) A solution of 5-nitro-1H-indole (Acros, 2.0 g, 13.5 mmol, 1.0eq) in DMF (125 mL) was cooled to 0° C., treated with sodium hydride(60% in mineral oil, 600 mg, 14.9 mmol, 1.1 eq) and stirred for 2.0hours. The resulting red solution was treated with allyl bromide (1.3mL, 14.9 mmol, 1.1 eq) and stirred for 1.0 hour at room temperature. Thereaction was diluted with water (1.0 L) and extracted with MTBE (3×500mL). The combined organic extracts were washed with water (500 mL),brine (200 mL), dried over magnesium sulfate, filtered and concentratedunder reduced pressure to give a brown oil (2.7 g). The crude productwas purified by radial chromatography over silica gel using 5-30% ethylacetate/cyclohexane to give 1-allyl-5-nitro-1H-indole, K-7a, as a lightyellow oil (2.5 g, 90%): TLC R_(f)=0.3 (5% ethyl acetate/cyclohexane);¹H NMR (300 MHz, CDCl₃) δ 6.60 (d, J=2.2 Hz, 1H), 8.11 (dd, 1H, J=9.2,2.2 Hz), 7.34 (d, 1H, J=9.2 Hz), 7.26-7.24 (m, 1H), 6.70 (d, 1H, J=3.3Hz), 6.06-5.94 (m, 1H), 5.26 (dd, 2H, J=10.3, 0.7 Hz), 5.08 (dd, 1H,J=17.3, 0.7 Hz), 4.79 (d, 2H, J=5.5 Hz); MS (FAB) m/z 203 [M+H]⁺.

[0330] (b) A mixture of water (20 mL), methanol (20 mL), zinc (4.2 g,64.2 mmol, 5.6 eq) and 1-allyl-5-nitro-1H-indole, K-7a, (2.3 g, 11.4mmol, 1.0 eq) was treated with concentrated sulfuric acid (6 mL, 333mmol, 29 eq) at 0° C. The mixture was gradually warmed to roomtemperature. After 18 hours, the mixture was filtered, and the pH of theresulting brown solution was adjusted to 9 with a saturated sodiumbicarbonate solution. The resulting slurry was filtered and extractedwith chloroform (3×500 mL). The combined organic extracts were washedwith brine (200 mL), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give a black oil (0.94 g). Thecrude product was purified by radial chromatography over silica gelusing 40% ethyl acetate/cyclohexane with 0.5% methanol to give1-allyl-1H-indol-5-ylamine, K-7b, as a dark brown oil (233 mg, 5%): TLCR_(f)=0.3 (30% ethyl acetate/cyclohexane); ¹H NMR (300 MHz, CDCl₃) δ7.16 (d, 1H, J=8.4 Hz), 7.07-7.03 (m, 2H), 6.77 (dd, 1H, J=8.6, 2.0 Hz),6.36 (d, 1H, J=2.9 Hz), 6.04-5.91 (m, 1H), 5.18 (dd, 1H, J=10.3, 1.1Hz), 5.05 (dd, 1H, J=16.9, 1.1 Hz), 4.67 (d, 2H, J=5.5 Hz), 3.8 (br s,2H); MS (FAB) m/z 171 [M−H]⁻.

EXAMPLE K-8 3-(Pyridin-3-yl)methoxy-N-quinolin-6-yl-benzamide

[0331]

[0332] Example K-8, which was obtained as a white solid in a 20% yield,was prepared in a similar manner to that described for K-1, except6-aminoquinoline (Fluka) was used in place of3-methyl-4-isopropylaniline in step (d), and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, in step (e): HPLC R_(t)=17.0 min.; TLC R_(f)=0.6(5% methanol/chloroform); ¹H NMR (300 MHz, DMSO-d₆) δ 10.60 (s, 1H),8.86 (d, 1H, J=3.3 Hz), 8.78 (s, 1H), 8.63-8.60 (m, 2H), 8.39 (d, 1H,J=8.5 Hz), 8.12-8.04 (m, 2H), 7.98 (d, 1H, J=8.1 Hz), 7.74-7.70 (m, 2H),7.67-7.49 (m, 3H), 7.37-7.34 (m, 1H), 5.32 (s, 2H); HRMS (FAB) calcd forC₂₂H₁₇N₃O₂ [M+H]⁺ 356.1399, found 384.1406.

EXAMPLE K-9 N-(2-Methyl-quinolin-6-yl)-3-(pyridin-3-yl)methoxy-benzamide

[0333]

[0334] Example K-9, which was obtained as a white solid in a 16% yield,was prepared in a similar manner to that described for K-1, except6-amino-2-methylquinoline (Maybridge) was used in place of3-methyl-4-isopropylaniline in step (d), and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, in step (e): HPLC R_(t)=19.9 min.; TLC R_(f)=0.2(3% methanol/chloroform); ¹H NMR (300 MHz, DMSO-d₆) δ 10.54 (s, 1H),8.77 (d, 1H, J=0.7 Hz), 8.62 (dd, 1H, J=4.8, 1.4 Hz), 8.52 (d, 1H, J=1.9Hz), 8.26 (d, 1H, J=8.8 Hz), 8.05-7.93 (m, 3H), 7.71-7.69 (m, 2H),7.66-7.43 (m, 3H), 7.36-7.33 (m, 1H), 5.32 (s, 2H), 2.69 (s, 3H); ¹³CNMR (125 MHz, DMSO-d₆) δ 165.4, 158.1, 157.4, 149.3, 149.2, 144.5,136.3, 135.8, 132.4, 129.7, 128.5, 126.3, 124.1, 123.6, 122.4, 120.4,118.1, 116.4, 114.1, 67.3, 24.7; HRMS (FAB) calcd for C₂₃H₁₉N₃O₂ [M+H]⁺370.1556, found 370.1549.

EXAMPLE K-10N-(4-Isopropyl-3-methyl-phenyl)-4-fluoro-3-(Isoquinolin-4-yl)methoxy-benzamide

[0335]

[0336] Example K-10 was prepared in a similar manner to that describedfor K-1, except 4-fluoro-3-hydroxybenzoic acid was used in place of3-hydroxybenzoic acid in step (d): ¹H NMR (300 MHz, CDCl₃) δ 9.28 (s,1H), 8.63 (s, 1H), 8.11 (d, 1H, J=8.23 Hz) 8.05 (d, 1H, J=8.11 Hz), 7.79(m, 2H), 7.68 (m, 2H), 7.40 (m, 3H), 7.22 (m, 2H), 5.60 (s, 2H), 3.12(br, 1H), 2.35 (s, 3H), 1.22 (d, 6H, J=6.9 Hz). MS (FAB) m/z 429 [M+H]⁺.Anal. calcd for C₂₇H₂₅FN₂O₂. 0.8H₂O: C, 73.22; H, 6.05; N, 6.33. Found:C, 73.21; H, 5.73; N, 6.19.

EXAMPLE K-11N-(4-Isopropyl-3-methyl-phenyl)-4-methyl-3-(Isoquinolin-4-yl)methoxy-benzamide

[0337]

[0338] Example K-11 was prepared in a similar manner to that describedfor K-1, except 4-methyl-3-hydroxybenzoic acid was used in place of3-hydroxybenzoic acid in step (d): ¹H NMR (300 MHz, CDCl₃) δ 9.29 (s,1H), 8.67 (s, 1H), 8.07 (s, 1H,) 8.04 (s, 1H), 7.80-7.64 (m, 4H),7.46-7.30 (m, 4H), 7.23 (m, 1H), 5.54 (s, 2H), 3.19-3.06 (m, 1H), 2.36(s, 3H), 2.25 (s, 3H), 1.23 (d, 6H, J=6.84 Hz). MS (ESI) m/z 425 [M+H]⁺.Anal. calc'd for C₂₈H₂₈N₂O₂: C, 79.22; H, 6.65; N, 6.60. Found: C,79.27; H, 6.74; N, 6.60.

EXAMPLE K-12N-(4-Isopropyl-3-methyl-phenyl)-4-chloro-3-(Isoquinolin-4-yl)methoxy-benzamide

[0339]

[0340] Example K-12 was prepared in a similar manner to that describedfor K-1, except 4-chloro-3-hydroxybenzoic acid was used in place of3-hydroxybenzoic acid in step (d): ¹H NMR (300 MHz, CDCl₃) δ 9.30 (br,s, 1H), 8.70 (br, s, 1H), 8.14-8.04 (m, 2H), 7.82-7.65 (m, 4H),7.50-7.32 (m, 4H), 7.23 (m, 1H), 5.61 (s, 2H), 3.13 (m, 1H), 2.36 (s,3H), 1.23 (d, 6H, J=6.89 Hz). EIMS m/z 444 [M⁺]. Anal. calc'd forC₂₇H₂₅ClN₂O₂: C, 72.88; H, 5.66; N, 6.30. Found: C, 72.86; H, 5.71; N,6.24.

EXAMPLE L-13-(6-Aminopyridin-3-yl)methoxy-N-(4-Isopropyl-3-methyl-phenyl)-benzamide

[0341]

[0342] (a) A solution of 6-chloronicotinic acid (Aldrich, 10.0 g, 63.7mmol, 1.0 eq) in dioxane (300 mL) was treated with a 1.0 M solution ofborane in THF (320 mL, 329 mmol, 5.0 eq) at room temperature. Theresultant orange solution was stirred for one hour and then heated to75° C. After 2.5 h, the reaction was quenched with ethanol (100 mL), andthe solvent was removed under reduced pressure. The crude product wasstirred in 1.2 M HCl (350 mL) and the pH was subsequently adjusted to 9with solid NaOH. The aqueous layer was extracted with ethyl acetate(3×200 mL) and the combined organic extracts were washed with water (200mL), brine (200 mL), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give a yellow oil (23.4 g). Thecrude product was purified by flash chromatography over silica gel using30-60% ethyl acetate/cyclohexane to give (6-chloropyridin-3-yl)methanol,L-1a, as a white crystalline solid (5.0 g, 54%): HPLC R_(t)=2.9 min.;TLC R_(f)=0.5 (5% methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ8.35 (d, 1H, J=1.9 Hz), 7.79 (dd, 1H, J=8.2, 2.4 Hz), 7.48 (d, 1H, J=8.2Hz), 5.42 (t, 1H, J=5.6 Hz), 4.53 (d, 2H, J=5.7 Hz); ¹³C NMR (75 MHz,DMSO-d₆) δ 148.9, 148.4, 138.5, 137.6, 124.2, 60.2; MS (ESI) m/z 144[M+H]⁺.

[0343] (b) A solution of the (6-chloropyridin-3-yl)-methanol, L-1a, (186mg, 1.3 mmol, 1.0 eq),3-hydroxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide, K-1d, (350 mg, 1.3mmol, 1.0 eq) and triphenylphosphine (1.0 g, 3.9 mmol, 3.0 eq) in THF(15 mL) was protected from light and treated with diethylazodicarboxylate (0.62 mL, 3.9 mmol, 3.0 eq). After 18 h, the resultantlight yellow solution was poured into 50% brine (200 mL) and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith brine (200 mL), dried over magnesium sulfate, filtered through asilica gel plug, and concentrated under reduced pressure to give ayellow oil (2.6 g). The crude product was purified by radialchromatography over silica gel using 5-10% ethyl acetate/45%cyclohexane/dichloromethane to give3-(6-chloropylidin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide,L-1b, as a white solid (380 mg, 74%): HPLC R_(t)=16.2 min.; TLCR_(f)=0.4 (30% ethyl acetate/cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ10.07 (s, 1H), 8.56 (d, 1H, J=2.3 Hz), 7.99 (dd, 1H, J=8.2, 2.4 Hz),7.60-7.44 (m, 6H), 7.27-7.19 (m, 2H), 5.25 (s, 2H), 3.31-3.03 (m, 1H),2.29 (s, 3H), 1.18 (d, 6H, J=6.9 Hz); ¹³C NMR (75 MHz, DMSO-d₆) δ 165.1,158.2, 150.2, 149.6, 142.2, 139.8, 136.8, 136.7, 135.0, 132.4, 130.0,125.0, 124.6, 122.5, 120.7, 118.8, 118.2, 114.2, 66.6, 28.7, 23.5, 19.5;MS (ESI) m/z 393 [M−H]⁻.

[0344] (c) A solution of3-(6-chloropyridin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide,L-1b, (300 mg, 0.76 mmol, 1.0 eq), 4-methoxybenzylamine (Aldrich, 0.12mL, 0.91 mmol, 1.2 eq), palladium acetate (Strem, 6.8 mg, 0.03 mmol, 4mol %), and CyMAP1 (J. Am. Chem. Soc. 1998, 120, 9722-23, 11.8 mg, 0.03mmol, 4 mol %) in dioxane (10 mL) was treated with sodium-tert-butoxide(169 mg, 1.82 mmol, 1.4 eq). The resultant orange solution was warmed to80° C. for 18 hours. The reaction mixture was poured into 50% brine (100mL) and extracted with ethyl acetate (3×75 mL). The combined organicextracts were washed with brine (200 mL), dried over magnesium sulfate,filtered through a silica gel plug, and concentrated under reducedpressure to give a yellow oil (330 mg). The crude product was purifiedby radial chromatography over silica gel using 45% ethylacetate/cyclohexane to give, from MTBE,N-(4-isopropyl-3-methyl-phenyl)-3-[6-{(4-methoxybenzyl)amino}pyridin-3-ylmethoxy]-benzamide,L-1c, as a white solid (189 mg, 50%): HPLC R_(t)=14.7 min.; TLCR_(f)=0.4 (4% methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ9.43 (s, 1H), 7.74 (s, 1H), 7.27-7.18 (m, 3H), 7.02-6.82 (m, 6H),6.70-6.62 (m, 4H), 6.41 (d, 1H, J=8.5 Hz), 4.79 (s, 2H), 4.32 (d, 2H,J=5.5 Hz), 3.69 (s, 3H), 2.97-2.90 (m, 1H), 2.13 (s, 3H), 1.05 (d, 6H,J=6.7 Hz); ¹³C NMR (75 MHz, DMSO-d₆) δ 169.9, 158.4, 158.3, 157.0,147.4, 144.8, 140.4, 138.0, 137.2, 135.7, 132.7, 129.0, 128.8, 125.8,125.3, 120.8, 119.2, 116.7, 115.5, 113.9, 108.2, 55.4, 50.7, 44.0, 28.7,23.3, 19.2; MS (ESI) m/z 494 [M−H]⁻.

[0345] (d) A solution ofN-(4-isopropyl-3-methyl-phenyl)-3-[6-{(4-methoxybenzyl)amino}pyridin-3-ylmethoxy]-benzamide,L-1c, (120 mg, 0.24 mmol) in trifluoroacetic acid (6 mL) was stirred atroom temperature. After 18 hours, the resultant cherry red solution wasconcentrated under reduced pressure and extracted with 50% sodiumbicarbonate (25 mL) and ethyl acetate (3×25 mL). The combined organicextracts were washed with 5% sodium bicarbonate (50 mL), brine (50 mL),dried over magnesium sulfate, and concentrated under reduced pressure togive a clear oil (132 mg). The crude product was purified by radialchromatography over silica gel using 5% methanol/chloroform with 0.1%ammonium hydroxide to give,3-(6-amino-pyridin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide,L-1, as a white solid (75 mg, 82%): mp 78-81° C.; HPLC R_(t)=12.1 min.;TLC R_(f)=0.4 (8% methanol/chloroform); ¹H NMR (300 MHz, DMSO-d₆) δ 9.32(s, 1H), 7.54 (d, 1H, J=2.0 Hz), 7.13 (dd, 1H, J=8.4, 2.4 Hz), 6.90-6.71(m, 2H), 6.58 (d, 1H, J=1.5 Hz), 6.54-6.47 (m, 4H), 6.23 (d, 1H, J=8.5Hz), 5.70 (s, 2H), 4.66 (s, 2H), 2.94-2.78 (m, 1H), 2.02 (s, 3H), 0.94(d, 6H, J=6.8 Hz); MS (ESI) m/z 494 [M−H]⁻. Anal. calcd forC₂₃H₂₅N₃O₂.0.4 hexane: C, 74.42; H, 7.52; N, 10.25. Found: C, 74.09; H,7.49; N, 10.00.

EXAMPLE M-13-(6-Aminopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide

[0346]

[0347] (a) A mixture of 6-chloronicotinic acid (Aldrich, 5.0 g, 31.6mmol, 1.0 eq), water (10 mL) and ethanol (35 mL) was treated with sodiumazide (2.15 g, 33.8 mmol, 1.1 eq). The resulting orange solution washeated to 75° C. After 18 h, the solvent was removed under reducedpressure and the resultant white slurry was repeatedly evaporated withtoluene to give the crude 6-azido-nicotinic acid/NaCl mixture, M-1a, asa white solid (6.9 g, 98%): TLC R_(f) 0.2 (6% methanol/dichloromethanew/ 0.1% Acetic acid); ¹H NMR (500 MHz, DMSO-d₆) δ 9.41 (s, 1H), 7.98 (s,1H), 7.97 (s, 1H).

[0348] (b) A mixture of 6-azidonicotinic acid/NaCl, M-1a, (6.9 g, 31.1mmol), and thionyl chloride (100 mL) was heated to 75° C. After 2 hours,the crude acid chloride hydrochloride salt was obtained by removing thethionyl chloride under pressure. The resultant slurry was evaporatedfrom toluene and then added to a slurry of isopropanol (100 mL) andsodium borohydride at −10° C. The resultant yellow slurry was warmed toroom temperature over several hours and stirred at room temperature for12 h. The reaction mixture was poured into water (500 mL) and extractedwith ethyl acetate (3×500 mL). The combined organic extracts were washedwith brine (200 mL), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give a yellow solid (2.3 g). Thecrude product was purified by radial chromatography over silica gelusing 1-3% methanol/dichloromethane to give(6-azidopyridin-3-yl)-methanol, M-1b, as a white solid (850 mg, 18%):TLC R_(f)=0.4 (5% methanol/chloroform); ¹H NMR (500 MHz, DMSO-d₆) δ 9.14(s, 1H), 8.19 (d, 1H, J=9.0 Hz), 7.84 (dd, 1H, J=9.4, 1.0 Hz), 5.67 (t,1H, J=5.6 Hz), 4.66 (d, 2H, J=5.6 Hz).

[0349] (c) A solution of (6-azidopyridin-3-yl)-methanol, M-1b, (350 mg,2.3 mmol, 1.0 eq) in THF (25 mL) was cooled to −78° C. and treated withmesyl chloride (265 μL, 3.4 mmol, 1.5 eq). After 60 minutes at −78° C.,the clear solution was treated with triethylamine (0.70 mL, 5.1 mmol,2.2 eq), and the reaction mixture was warmed to −20° C. over 2.5 hours.The resultant cloudy reaction mixture was monitored by TLC (3%methanol/dicbloromethane), which gave only product (R_(f) 0.4) and nostarting material (R_(f) 0.2). To obtain an analytical sample, analiquot of the reaction mixture was diluted in 25% ammonium acetate andextracted with ethyl acetate. The organic extract was washed with water,brine, dried over magnesium sulfate, filtered and concentrated underreduced pressure to give (6-azidopyridin-3-yl)methyl methanesulfonate,M-1c, as a tan solid: TLC R_(f)=0.6 (5% methanol/chloroform); ¹H NMR(500 MHz, DMSO-d₆) δ 9.5 (s, 1H), 8.30 (d, 1H, J=9.4 Hz), 7.94 (d, 1H,J=9.6 Hz), 5.46 (s, 2H), 3.35 (s, 3H).

[0350] (d) A solution of 3-acetoxybenzoic acid (Aldrich, 1.8 g, 9.9mmol, 1.0 eq) and 6-amino-2-methylquinoline (Avocado, 1.6 g, 9.9 mmol,1.0 eq) in ethyl acetate (50 mL) was treated with a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g, 11.8mmol, 1.2 eq) in dichloromethane (50 mL). After 18 h, the resultant tanslurry was poured into 5% sodium bicarbonate (200 mL) and extracted with10% isopropyl alcohol/chloroform (3×150 mL). The combined organicextracts were washed with brine (200 mL), dried over magnesium sulfate,filtered through a silica gel plug and concentrated under reducedpressure to give a yellow solid (2.8 g). The crude product was purifiedby radial chromatography over silica gel using 1-2%methanol/dichloromethane to give an unpure product as a yellow solid(2.6 g). The unpure product was washed with MTBE and the solids werecollected to give 3-acetoxy-N-(2-methyl-quinolin-6-yl)benzamide, M-1d,as a light yellow solid (2.3 g, 84%): HPLC R_(t)=11.2 min.; TLCR_(f)=0.3 (3% methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ10.40 (s, 1H), 8.29 (d, 1H, J=2.2 Hz), 8.04 (d, 1H, J=8.5 Hz), 7.83-7.72(m, 3H), 7.59 (t, 1H, J=1.8 Hz), 7.45 (t, 1H, J=7.9 Hz), 7.24 (d, 1H,J=8.4 Hz), 2.48 (s, 3H), 2.16 (s, 3H); MS (ESI) m/z 321 [M+H]⁺.

[0351] (e) A solution of 3-acetoxy-N-(2-methyl-quinolin-6-yl)benzamide,M-1d, (2.2 g, 6.9 mmol, 1.0 eq) in methanol (65 mL) and THF (60 mL) wastreated with a solution of potassium carbonate (4.8 g, 34.5 mmol, 5.0eq) in water (45 mL). After 3.0 h, the cloudy reaction mixture wasconcentrated under reduced pressure and extracted with water (100 mL)and ethyl acetate (3×100 mL). The combined organic extracts were washedwith brine (200 mL), dried over magnesium sulfate and concentrated underreduced pressure to give a light yellow solid (2.0 g). The crude productwas washed with dichloromethane and the solids were collected to give3-hydroxy-N-(2-methyl-quinolin-6-yl)-benzamide, M-1e, as a light yellowsolid (1.6 g, 83%): HPLC R_(t)=9.5 nm.; TLC R_(f)=0.3 (5%methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ 10.43 (s, 1H),9.78 (s, 1H), 8.47 (d, 1H, J=2.2 Hz), 8.20 (d, 1H, J=8.4 Hz), 8.00-7.87(m, 2H), 7.44-7.32 (m, 4H), 7.01-6.98 (m, 1H), 2.64 (s, 3H); ¹³C NMR (75MHz, DMSO-d₆) δ 166.2, 157.7, 157.6, 144.8, 136.8, 136.6, 136.1, 129.8,128.8, 126.7, 124.4, 122.8, 119.0, 118.6, 116.6, 114.9, 25.0; MS (ESI)m/z 279 [M+H]⁺.

[0352] (f) A mixture of 3-hydroxy-N-(2-methyl-quinolin-6-yl)-benzamide,M-1e, (0.64 g, 2.3 mmol, 1.0 eq) and cesium carbonate (3.0 g, 9.2 mmol,4.0 eq) in acetone (45 mL) was treated with unpurified(6-azidopyridin-3-yl)methyl methanesulfonate, M-1c, (524 mg, 2.3 mmol,1.0 eq). After 18 h at 50° C., the resultant pink slurry was poured into5% sodium bicarbonate (400 mL) and extracted with 5% isopropylalcohol/chloroform (3×300 mL). The combined organic extracts were washedwith brine (300 mL), dried over magnesium sulfate and concentrated underreduced pressure to give a light yellow solid (0.99 g). The crudeproduct was washed with diethyl ether and the solids were collected togive3-(6-azidopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide,M-1f, as a light yellow solid (0.87 g, 92%): HPLC R_(t)=11.7 min.; TLCR_(f)=0.5 (5% methanol/dichloromethane); ¹H NMR (500 MHz, DMSO-d₆) δ10.51 (s, 1H), 9.53 (s, 1H), 8.46 (d, 1H, J=2.0 Hz), 8.30 (d, 1H, J=9.2Hz), 8.21 (d, 1H, J=9.0 Hz), 8.02-7.98 (m, 2H), 7.91 (d, 1H, J=9.1 Hz),7.72 (s, 1H), 7.66 (d, 1H, J=7.8 Hz), 7.54 (t, 1H, J=8.0 Hz), 7.40 (d,1H, J=8.4 Hz), 7.36 (dd, 1H, J=8.2, 2.0 Hz), 5.40 (s, 2H), 2.51 (s, 3H);MS (ESI) m/z 411 [M+H]⁺.

[0353] (g) A solution of3-(6-azidopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide,M-1f, (58 mg, 0.14 mmol, 1.0 eq) in anhydrous ethanol (20 mL) wastreated with tin(II) chloride dihydrate (158 mg, 0.70 mmol, 5.0 eq) andwarmed to 70° C. After 18 h, the light yellow solution was concentratedunder reduced pressure and treated with a saturated sodium bicarbonatesolution (100 mL). The aqueous layer was extracted with ethyl acetate(3×100 mL) and the combined organic extracts were washed with brine (200mL), dried over magnesium sulfate, filtered and concentrated underreduced pressure to give a white foam (60 mg). The crude product waspurified by radial chromatography over silica gel using 5%methanol/chloroform to give3-(6-aminopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide,M-1, as a white solid (23 mg, 42%): mp 189-192° C.; HPLC R_(t)=11.4min.; TLC R_(f)=0.3 (5% methanol/chloroform); ¹H NMR (500 MHz, DMSO-d₆)δ 10.48 (s, 1H), 8.49 (d, 1H, J=2.0 Hz), 8.22 (d, 1H, J=8.5 Hz), 8.05(d, 1H, J=1.8 Hz), 8.00 (dd, 1H, J=9.1, 2.2 Hz), 7.92 (d, 1H, J=9.1 Hz),7.64-7.41 (m, 4H), 7.41 (d, 1H, J=8.4 Hz), 7.26 (dd, 1H, J=8.2, 1.9 Hz),6.49 (d, 1H, J=8.4 Hz), 6.05 (s, 2H), 5.01 (s, 2H), 2.66 (s, 3H); MS(ESI) m/z 385 [M+H]⁺.

[0354] Anal. calcd for C₂₃H₂₀N₄O₂.0.5H₂O: C, 70.21; H, 5.38; N, 14.24.Found: C, 70.42; H, 5.34; N, 13.85.

EXAMPLE N-13-(6-Acetylaminopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide

[0355]

[0356] A cloudy suspension of3-(6-amino-pyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide,M-1, (40 mg, 0.10 mmol) in acetic anhydride (5 mL), THF (5 mL) anddichloromethane (3 mL) was stirred at room temperature. After 18 h, theresultant yellow solution was concentrated under reduced pressure andchased with toluene to give a yellow solid (56 mg). The crude productwas purified by radial chromatography over silica gel using 3-10%methanol/dichloromethane to give3-[6-(acetylaminopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide,N-1, as a white solid (40 mg, 91%): HPLC R_(t)=11.5 min.; TLC R_(f)=0.5(8% methanol/chloroform); ¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s, 1H),10.56 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.29 (d, 1H, J=8.4 Hz), 8.18(d, 1H, J=8.6 Hz), 8.07-7.95 (m, 3H), 7.71-7.67 (m, 2H), 7.56 (t, 1H,J=8.0 Hz), 7.47 (d, 1H, J=8.1 Hz), 7.35 (d, 1H, J=7.2 Hz), 5.25 (s, 2H),2.71 (s, 3H), 2.71 (s, 3H); MS (ESI) m/z 427 [M+H]⁺. Anal. calc'd forC₂₅H₂₂N₄O₃.0.1H₂O: C, 70.11; H, 5.23; N, 13.08. Found: C, 69.71; H,5.33; N, 12.82.

EXAMPLE N-23-(6-Acetylaminopyridin-3-yl)methoxy-N-(4-Isopropyl-3-methyl-phenyl)-benzamide

[0357]

[0358] A clear solution of3-(6-amino-pyridin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide,L-1, (30 mg, 0.08 mmol) in acetic anhydride (1.0 mL) was stirred at roomtemperature for 18 h. The resultant clear solution was concentratedunder reduced pressure and chased with toluene to give a clear oil. Thecrude product was extracted with 5% sodium bicarbonate (25 mL) and ethylacetate (3×25 mL). The combined ethyl acetate extracts were dried usingbrine (25 mL) and magnesium sulfate to give a clear oil (30 mg), whichwas identified as3-(6-diacetylamino-pyridin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamideby MS (ESI) (m/z 460). After purification by radial chromatography oversilica gel, the diacetylated compound (24 mg, 0.05 mmol, 1.0 eq) wasdissolved in methanol (0.5 mL) and treated with calcium carbonate (10mg, 0.1 mmol, 2.1 eq) and water (0.5 mL). The resultant white slurry washeated at 60° C. for 18 hours. The reaction mixture was poured intowater (25 mL) and extracted with ethyl acetate (3×25 mL). The combinedorganic extracts were washed with brine (50 mL), dried over magnesiumsulfate, and concentrated under reduced pressure to give a clear oil (40mg). The crude product was purified by radial chromatography over silicagel using 2-5% methanol/dichloromethane to give3-(6-acetylaminopyridin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide,N-2, as a white solid (20 mg, 61%): mp 98-101° C.; HPLC R_(t)=12.4 min.;¹H NMR (300 MHz, DMSO-d₆) δ 10.51 (s, 1H), 9.54 (s, 1H), 8.19 (s, 1H),8.06 (d, 1H, J=8.2 Hz), 7.72 (d, 1H, J=8.3 Hz), 7.11-6.97 (m, 3H),6.82-6.71 (m, 4H), 5.04 (s, 2H), 3.08-3.01 (m, 1H), 2.22 (s, 3H), 2.13(s, 3H), 1.13 (d, 6H, J=6.7 Hz); MS (ESI) m/z 418 [M+H]⁺. Anal. calc'dfor C₂₅H₂₇N₃O₃.0.4 hexane •0.5H₂O: C, 71.39; H, 7.35; N, 9.12. Found: C,71.11; H, 7.48; N, 8.70.

EXAMPLE O-14-Fluoro-N-(1,2,3,4-tetrahydroquinolin-6-yl)-3-(isoquinolin-4-yl-methoxy)-benzamideBistrifluoroacetic Acid Salt

[0359]

[0360] (a) To a stirred mixture of 4-fluoro-3-hydroxy-benzoic acid (0.73g, 4.7 mmol) and Cs₂CO₃ (4.58 g, 14.1 mmol) in dioxane/H₂O (1:1, 20 ml)was added 1.0 g (4.7 mmol) of 4-chloromethyl-isoquinoline•HCl, K-1c.After heating at 65° C. for 24 hrs, the solvent was removed, water wasadded, the pH was adjusted to 6, and the solution was extracted withethyl acetate (30 ml×3). The combined extracts were washed with 1N HCl.A precipitate formed and was filtered and dried to provide 0.41 g (29%)of 4-fluoro-3-(isoquinolin-4-yl)methoxy-benzoic acid hydrochloride,O-1a, as a solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.84 (s, 1H), 8.79 (s,1H), 8.54 (d, J=8.1 Hz, 1H), 8.44 (d, J=8.36 Hz, 1H), 8.21 (m, 1H), 8.02(m, 2H), 7.65 (m, 1H), 7.40 (dd, J=11.00, 8.46 Hz, 1H), 5.865 (s, 2H).

[0361] (b) To an ice cooled solution of 0.45 g (1.85 mmol) of6-(2,2,2-trifluoroacetylamino)-1,2,3,4-tetrahydroquinoline (Forbes, etal., J. Med. Chem., 38, 2524 (1995)) in THF (20 ml) was addeddi-t-butyl-dicarbonate (0.89 g, 4.08 mmol). After refluxing for 24 h,the solvent was removed and the residue was purified on silica gel usinga gradient of 0% to 2% ethyl acetate in dichloromethane as eluant toobtain 0.42 g (66%) of1-(tert-butoxycarbonyl)-6-(2,2,2-trifluoroacetylamino)-1,2,3,4-tetrahydroquinoline,O-1b, as a solid: ¹H NMR (300 MHz, CDCl₃) δ 7.78 (br s, 1H), 7.71 (d,J=8.9 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.19 (dd, J=8.9, 2.6 Hz, 1H),3.70 (m, 2H), 2.77 (t, J=6.5 Hz, 2H), 1.90 (t, J=6.4 Hz, 2H), 1.52 (s,9H).

[0362] (c) To stirred solution of 0.41 g (1.19 mmol) of1-(tert-butoxycarbonyl)-6-(2,2,2-trifluoro-acetylamino)-1,2,3,4-tetrahydroquinoline,O-1b, in methanol (20 ml) was added K₂CO₃ (0.25 g, 1.79 mmol). Afterrefluxing for 24 h, the methanol was removed, followed by addition ofwater and ethyl acetate. The layers were separated, and the aqueouslayer was extracted with ethyl acetate. The combined extracts werewashed with brine, dried over MgSO₄, and concentrated to leave 0.228 g(77%) of 6-amino-1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline,O-1c, as an oil: ¹H NMR (300 MHz, CDCl₃) δ 7.38 (d, J=8.5 Hz, 1H), 6.47(dd, J=8.7, 2.7 Hz, 1H), 6.39 (m, 1H), 3.64 (m, 2H), 3.40 (brs, 1H),2.65 (t, J=6.6 Hz, 2H), 1.86 (t, J=6.2 Hz, 2H), 1.50, (s, 9H).

[0363] (d) A solution of 0.35 g (1.17 mmol) of4-fluoro-3-(isoquinolin-4-yl)methoxy-benzoic acid hydrochloride, O-1a,in SOCl₂ (5 ml) was stirred and heated at 60° C. for 3 h. The thionylchloride was removed under reduced pressure to provide crude acidchloride O-1d, which was dissolved in dichloromethane (15 ml) underargon. The solution was cooled to 0° C. followed by addition of 0.260 g(1.07 mmol) of6-amino-1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline, O-1c, anddiisopropylethylamine (0.3 g, 2.34 mmol). After stirring for 24 hrs,dichloromethane (15 ml) was added, and the solution was washed with sat.NaHCO₃, and dried over sodium sulfate and concentrated. The residue waspurified on silica gel using a gradient of 0% to 5% ethyl acetate indichloromethane as eluant to obtain 0.190 g (30%) of4-fluoro-N-{1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-6-yl}-3-(isoquinolin-4-yl-methoxy)-benzamide,O-1e.

[0364] (e) A solution of O-1e (0.185 g, 0.35 mmol) in 4N HCl in dioxane(5 ml) was stirred for 6 hrs at 0° C. The solvent was removed underreduced pressure to give 0.123 g (82%) of4-Fluoro-N-(1,2,3,4-tetrahydroquinolin-6-yl)-3-(isoquinolin-4-yl-methoxy)-benzamidehydrochloride as a solid. This product was further purified onsemi-preparative C18-reverse phase HPLC eluting with 5 to 95%acetonitrile/water containing 0.1% trifluoroacetic acid to provide4-fluoro-N-(1,2,3,4-tetrahydroquinolin-6-yl)-3-(isoquinolin-4-yl-methoxy)-benzamidebistrifluoroacetic acid salt, O-1: ¹H NMR (300 MHz, DMSO-d₆) δ 10.59 (s,1H), 9.81 (s, 1H), 8.83 (s, 1H), 8.52 (d, 1H, J=8.37 Hz) 8.45 (d, 1H,J=8.59 Hz), 8.24-8.17 (m, 2H), 8.01 (dd, 1H, J=7.35 Hz, J=7.6 Hz),7.79-7.70 (m, 3H), 7.43 (dd, 1H, J=10.87 Hz, J=10.7 Hz), 7.25 (d, 1H,J=8.46 Hz), 5.93 (s, 2H), 3.73-3.64 (m, 1H), 3.52-3.45 (m, 1H),3.37-3.35 (m, 1H), 2.87-2.83 (m, 2H), 2.02-1.94 (m, 2H). MS (ESI) m/z428 [M]⁺. Anal. calc'd for C₂₆H₂₂FN₃O₂.2 CF₃CO₂H.0.8H₂O: C, 53.78; H,3.85; N, 6.27. Found: C, 53.58; H, 4.00; N, 6.20.

EXAMPLE O-2N-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-3-(2-isoquinolin-4-yl-ethyl)-benzamideTrifluoro-Acetic Acid Salt

[0365]

[0366] Example O-2 was prepared in a similar manner to that describedfor O-1, except that 4-amino(2,2-difluoro-benzo[1,3]dioxole was used inplace of 6-amino-1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline,O-1c, and 3-{2-(isoquinolin-4-yl)ethyl}benzoic acid, S-1e (from exampleS-1 below), was used in place of4-fluoro-3-(isoquinolin-4-yl)methoxy-benzoic acid, O-1a, in step (d),and the final deprotection step was not needed: ¹H NMR (300 MHz,DMSO-d₆) δ 10.70 (s, 1H), 9.88 (s, 1H), 8.63-8.51 (m, 3H), 8.26 (dd, 1H,J=8.3 Hz, J=8.5 Hz), 8.05 (m, 2H), 7.87 (m, 1H), 7.62-7.43 (m, 2H),7.31-7.25 (m, 3H), 3.62-3.51 (m, 2H), 3.17-3.09 (m, 2H). MS (ESI) m/z433 [M]⁺. Anal. calc'd for C₂₅H₁₈ F₂N₂O₃.C₂F₃OOH: C, 59.35; H, 3.50; N,5.31. Found: C, 59.35; H, 3.60; N, 5.12.

EXAMPLE O-34-Fluoro-N-(2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(isoquinolin-4-yl-methoxy)-benzamideBistrifluoroacetic Acid Salt

[0367]

[0368] Example O-3 was prepared in a similar manner to that describedfor O-1, except that6-amino-1-(tert-butoxycarbonyl)-2-methyl-1,2,3,4-tetrahydroquinoline wasused in place of6-amino-1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinoline in step (d):¹H NMR (300 MHz, DMSO-d₆) δ 10.15 (s, 1H), 9.54 (s, 1H), 8.73 (s, 1H),8.35-8.26 (m, 2H), 8.04-7.98 (m, 2H), 7.86 (dd, 1H, J=7.12 Hz, J=7.08Hz), 7.67-7.62 (m, 1H), 7.52-7.49 (m, 2H), 7.41 (dd, 1H, J=10.96 Hz,J=10.99 Hz), 6.90 (d, 1H, J=8.37 Hz), 5.78 (s, 2H), 3.46 (m, 1H),2.87-2.68 (m, 2H), 2.01-1.97 (m, 1H), 1.69-1.63 (m, 1H), 1.27 (d, 3H,J=6.41 Hz). MS (ESI) m/z 442 [M]⁺. Anal. calc'd for C₂₇H₂₄FN₃O₂.2CF₃CO₂H: C, 55.61; H, 3.91; N, 6.28. Found: C, 55.51; H, 3.88; N, 6.22.

EXAMPLE P-1 N′-{4-[3-(4-Isopropyl-3-methyl-phenylcarbamoyl)-phenoxy

[0369]

[0370] (a) A solution of 4-bromoisoquinoline (Aldrich, 7.7 g, 37.0 mmol,1.0 eq) and perrhenic acid (70% in H₂O, 33 μL, 0.2 mmol, 0.5 mol %) indichloromethane (20 mL) was treated with bis(trimethylsilyl)peroxide(Gelest, 9.9 g, 55.5 mmol, 1.5 eq). After 18 hours, the resultant yellowsuspension was cooled to 0° C. and diluted with cyclohexane (30 mL). Thesolids were collected and washed with cold cyclohexane to give4-bromoisoquinoline N-oxide, P-1a, as a yellow solid (7.1 g, 86%): HPLCR_(t)=7.7 min.; TLC R_(f)=0.5(5% methanol/dichloromethane); ¹H NMR (300MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.58 (d, 1H, J=1.7 Hz), 7.97-7.87 (m, 2H),7.74-7.67 (m, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 138.6, 135.5, 130.6,130.2, 129.6, 127.4, 126.0, 125.7, 120.1; MS (ESI) m/z 224/226 [M+H]⁺.

[0371] (b) A yellow suspension of 4-bromoisoquinoline N-oxide, P-1a,(6.9 g, 30.8 mmol. 1.0 eq) in 1,2-dichloroethane (60 mL) was treatedwith phosphorus oxychloride (Aldrich, 9.0 mL, 96.4 mmol, 1.8 eq) andwarmed to 80° C. After 1.5 hours, the resultant green suspension wascarefully poured into a cold solution of 50% saturated sodiumbicarbonate (500 mL) and the aqueous layer was extracted with diethylether (3×300 mL). The combined organic extracts were washed with water(200 mL), brine (200 mL), dried over magnesium sulfate, and concentratedunder reduced pressure to give a tan solid (6.8 g). The crude productwas dissolved in a minimal amount of dichloromethane and purified byflash chromatography over silica gel using 5% ether/cyclohexane to give4-bromo-1-chloro-isoquinoline, P-1b, as a white solid (5.7 g, 77%): HPLCR_(t)=15.4 min.; TLC R_(f)=0.4 (5% ether/cyclohexane); ¹H NMR (300 MHz,DMSO-d₆) δ 8.68 (s, 1H), 8.42 (d, 1H, J=8.4 Hz), 8.26 (d, 1H, J=8.3 Hz),8.15 (t, 1H, J=7.6 Hz), 8.02 (t, 1H, J=7.6 Hz); ¹³C NMR (75 MHz,DMSO-d₆) δ 150.4, 143.0, 135.8, 133.8, 130.8, 127.3, 126.8, 126.5,119.0; MS (ESI) m/z 242/244 [M+H]⁺.

[0372] (c) 1-Chloro-isoquinoline-4-carbaldehyde, P-1c, which wasobtained as a white solid in a 95% yield, was prepared in a similarmanner to that described for isoquinoline-4-carbaldehyde, K-1a, inexample K-1, except that 4-bromo-1-chloro-isoquinoline, P-1b, was usedin place of 4-bromoisoquinoline: HPLC R_(t)=11.9 min.; TLC R_(f)=0.6(20% ethyl acetate/cyclohexane); ¹H NMR (300 MHz, DMSO-d₆) δ 10.40 (s,1H), 9.15 (d, 1H, J=8.5 Hz), 8.93 (s, 1H), 8.46 (d, 1H, J=8.5 Hz), 8.12(t, 1H, J=7.1 Hz), 8.00 (t, 1H, J=7.8 Hz); ¹³C NMR (75 MHz, DMSO-d₆) δ193.6, 156.5, 151.4, 134.8, 133.9, 130.4, 126.9, 126.0, 124.9, 124.6; MS(ESI) m/z 192 [M+H]⁺.

[0373] (d) (1-Chloro-isoquinolin-4-yl)-methanol, P-1d, which wasobtained as a white solid in a 96% yield, was prepared in a similarmanner to that described for isoquinolin-4-yl-methanol, K-1b, exceptthat 1-chloro-isoquinoline-4-carbaldehyde, P-1c, was used in placeisoquinoline-4-carbaldehyde, K-1a: HPLC R_(t)=9.0 min.; TLC R_(f)=0.2(2% methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (d, 1H,J=8.5 Hz), 8.50 (s, 1H), 8.42 (d, 1H, J=8.3 Hz), 8.15 (t, 1H, J=7.6 Hz),8.05 (t, 1H, J=7.6 Hz), 5.71 (br s, 1H), 5.15 (s, 2H); ¹³C NMR (75 MHz,DMSO-d₆) δ 150.1, 140.0, 136.0, 131.9, 131.8, 129.3, 126.3, 125.8,124.6, 59.0; MS (ESI) m/z 194 [M+H]⁺.

[0374] (e)3-(1-Chloro-isoquinolin-4-ylmethoxy)-N-(4-isopropyl-3-methyl-phenyl)-benzamide,P-1e, which was obtained as a white solid in a 64% yield, was preparedin a similar manner to that described for3-(6-chloropyridin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide,L-1b, except that (1-chloro-isoquinolin-4-yl)-methanol, P-1d, was usedin place of (6-chloropyridin-3-yl)-methanol, L-1a: HPLC R_(t)=18.0 min.;TLC R_(f)=0.5 (5% ethyl acetate/45% dichloromethane/cyclohexane); ¹H NMR(300 MHz, DMSO-d₆) δ 10.06 (s, 1H), 8.52 (s, 1H), 8.38 (d, 1H, J=8.5Hz), 8.25 (d, 1H, J=8.3 Hz), 8.01 (t, 1H, J=7.6 Hz), 7.90 (t, 1H, J=8.2Hz), 7.68 (s, 1H), 7.61-7.46 (m, 4H), 7.35 (d, 1H, J=7.9 Hz), 7.20 (d,1H, J=8.4 Hz), 5.65 (s, 2H), 3.12-3.05 (m, 1H), 2.29 (s, 3H), 1.17 (d,6H, J=6.9 Hz); ¹³C NMR (75 MHz, DMSO-d₆) δ 165.1, 158.4, 151.5, 142.2,141.9, 136.8, 136.7, 136.3, 135.0, 132.6, 130.0, 129.8, 127.1, 126.6,126.1, 125.0, 124.7, 122.5, 120.8, 118.9, 118.3, 114.3, 65.6, 28.7, 27.2MS (ESI) m/z 443 [M−H]⁻.

[0375] (f) A mixture of3-(1-chloro-isoquinolin-4-ylmethoxy)-N-(4-isopropyl-3-methyl-phenyl)-benzamide,P-1e, (50 mg, 0.11 mmol, 1.0 eq), tert-butyl carbazate (75 mg, 0.56mmol, 5.0 eq) and para-toluenesulfonic acid monohydrate (31 mg, 0.16mmol, 1.5 eq) in isopropyl alcohol (1.5 mL) was warmed to 60° C. After4.5 h the resultant white suspension was poured into 5% sodiumbicarbonate (25 mL) and extracted with ethyl acetate (3×25 mL). Thecombined organic extracts were washed sequentially with water (25 mL),sodium citrate (0.5 M, pH 4.5, 25 mL), water (25 mL) and brine (25 mL).The organic extracts were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to give a clear oil (90 mg). Thecrude product was purified by radial chromatography over silica gelusing 2-3% methanol/dichloromethane to give, from methyl tert-butylether,N′-{4-[3-(4-isopropyl-3-methyl-phenylcarbamoyl)-phenoxymethyl]-isoquinolin-1-yl}-hydrazinecarboxylicacid tert-butyl ester, P-1, as a white solid (55 mg, 93%): mp 125-129°C.; HPLC R_(t)=16.5 min.; TLC R_(f)=0.5 (4% methanol/dichloromethane);¹H NMR (300 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.35 (s, 1H), 8.78 (s, 1H),8.33 (d, 1H, J=8.3 Hz), 8.10 (s, 1H), 7.96 (d, 1H, J=8.3 Hz), 7.76 (t,1H, J=7.6 Hz), 7.64-7.27 (m, 7H), 7.20 (d, 1H, J=8.4 Hz), 5.41 (s, 2H),3.09-3.05 (m, 1H), 2.29 (s, 3H), 1.40 (s, 9H), 1.17 (d, 6H, J=6.8 Hz);¹³C NMR (75 MHz, DMSO-d₆) δ 165.8, 159.4, 157.2, 155.6, 143.8, 141.5,137.1, 136.3, 136.1, 135.6, 131.2, 130.2, 127.1, 125.7, 124.2, 122.4,122.3, 119.7, 119.0, 118.6, 118.5, 117.8, 113.9, 81.9, 67.3, 29.3, 28.6,27.3, 23.6, 19.8; MS (ESI) m/z 541 [M+H]⁺. Anal. calc'd forC₃₂H₃₆N₄O₄.0.25 hexane: C, 71.57; H, 7.08; N, 9.97. Found: C, 71.38; H,7.18; N, 9.66.

EXAMPLE Q-1N-(4-Isopropyl-3-methyl-phenyl)-3-{1-[N′-(3-methoxy-benzylidene)-hydrazino]-isoquinolin-4-ylmethoxy}-benzamide

[0376]

[0377] A solution ofN′-{4-[3-(4-isopropyl-3-methyl-phenylcarbamoyl)-phenoxymethyl]-isoquinolin-1-yl}-hydrazinecarboxylicacid tert-butyl ester, P-1, (94 mg, 0.21 mmol, 1.0 eq) indichloromethane (2.0 mL) was treated with trifluoroacetic acid (0.5 mL).After 1.5 hours, the resultant yellow solution was carefully poured into5% sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×25mL). The combined organic extracts were washed with brine (25 mL), driedover magnesium sulfate, and concentrated under reduced pressure to givea yellow solid (97 mg). The crude product was dissolved in ethyl alcohol(4 mL) and treated with acetic acid (3 drops), and 3-methoxybenzaldehyde(Aldrich, 40 μL, 0.32 mmol, 1.5 eq). After 18 hours, the resultantyellow suspension was poured into 5% sodium bicarbonate (25 mL). Theaqueous layer was diluted with brine (15 mL) and extracted with ethylacetate (3×25 mL). The combined organic extracts were washed with brine(50 mL), dried over magnesium sulfate, and concentrated under reducedpressure to give a yellow residue (128 mg). The crude product waspurified by radial chromatography over silica gel using 1-2%methanol/dichloromethane to giveN-(4-isopropyl-3-methylphenyl)-3-{1-[N′-(3-methoxybenzylidene)hydrazino]isoquinolin-4-yl}methoxy-benzamide,Q-1, as a yellow solid (25 mg, 21%): mp 125-129° C.; HPLC R_(t)=18.3min.; TLC R_(f)=0.5 (4% methanol/dichloromethane); ¹H NMR (300 MHz,DMSO-d₆) δ 10.94 (s, 1H), 8.43 (br s, 2H), 7.65-7.22 (m, 13H), 7.20 (d,1H, J=8.4 Hz), 6.99 (d, 1H, J=8.2 Hz), 5.24 (s, 2H), 3.84 (s, 3H),3.10-3.05 (m, 1H), 2.29 (s, 3H), 1.17 (d, 6H, J=6.8 Hz); MS (ESI) m/z559 [M+H]⁺. Anal. calc'd for C₃₅H₃₄N₄O₃.0.5 hexane: C, 75.84; H, 6.87;N, 9.31. Found: C, 75.81; H, 6.89; N, 9.09.

EXAMPLE R-1N-(3,5-Diallyl-4-methyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide

[0378]

[0379] (a) To a solution of 1.0 g (4.7 mmol) of4-(chloromethyl)isoquinoline hydrochloride, K-1c, in DMF (10 mL) andacetone (25 mL) was added methyl 3-hydroxybenzoate (800 mg, 5.3 mmol)and cesium carbonate (3.8 g, 11.7 mmol). After refluxing for 20 h thesolution was cooled, concentrated and diluted with dichloromethane. Thesolution was washed with sodium bicarbonate and brine. After drying overthe sodium sulfate the product was precipitated from diethylether/hexanes yielding 1.15 grams (84% yield) of methyl3-(isoquinolin-4-yl)methoxy-benzoate, R-1a, as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.67 (s, 1H), 8.20 (d, J=8.0 Hz, 1H),8.15 (d, J=8.6 Hz, 1H), 7.88 (ddd, J=7.0, 7.0, 1.3 Hz, 1H), 7.75 (ddd,J=7.5, 7.5, 1.0 Hz, 1H), 7.65 (m, 1H), 7.60 (m, 1H), 7.49 (dd, J=8.1 Hz,1H), 7.41 (m, 1H), 5.64 (s, 2H), 3.86 (s, 3H).

[0380] (b) To methyl 3-(isoquinolin-4-yl)methoxy-benzoate, R-1a, (2.24g, 7.64 mmol) in 95% EtOH (50 mL) was added 1 N NaOH (8 ml). Afterstirring for two hours at 70° C. the solution was cooled andconcentrated to about 10 mL. With ice cooling the solution was acidifiedwith 1N HCl. The resulting white precipitate was filtered yielding 1.3 gof 3-(isoquinolin-4-yl)methoxy-benzoic acid hydrochloride, R-1b, as awhite solid. Extraction of the mother liquors with dichloromethane threetimes resulted in 480 mg more product. (74% overall yield). ¹H NMR (300MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.81 (s, 1H), 8.50 (d, J=8.2 Hz, 1H), 8.39(d, J=8.5 Hz, 1H), 8.18 (dd, J=8.4, 8.4 Hz, 1H), 7.99 (dd, J=7.5, 7.5Hz, 1H), 7.69 (m, 1H), 7.61 (m, 1H), 7.48 (dd, J=8.1, 8.1 Hz, 1H), 7.41(m, 1H), 5.76 (s, 2H).

[0381] (c) To a solution of 72 mg (0.38 mmol)3,5-diallyl-4-methylaniline, prepared as described in steps (d) through(f) below, in DMF (6 mL) was added 120 mg (0.380 mmol) of3-(isoquinolin-4-ylmethoxy)-benzoic acid hydrochloride, R-1b, 160 μL(0.92 mmol) of diisopropylethylamine and PyBop,(240 mg, 0.46 mmol).After stirring for 2.5 h, DMAP (3 mg) was added. At five hours all but 3mL of solvent was removed, and the remaining solution was diluted withdichloromethane (40 ml) and washed with water, and brine. After dryingover sodium sulfate, the solution was concentrated and chromatographedwith silica gel eluting with 20 to 40% ethyl acetate/dichloromethaneyielding 130 mg (75% yield) ofN-(3,5-diallyl-4-methyl-phenyl)-3-(3soquinolin-4-yl)methoxy-benzamide,R-1, as a white foam. ¹H NMR.(300 MHz, CDCl₃) δ 9.29 (s, 1H), 8.63 (s,1H), 8.06 (m, 2H), 7.79 (m, 1H), 7.62-7.82 (m, 3H), 7.44 (m, 2H), 7.35(s, 2H), 7.23 (m, 1H), 5.97 (m, 2H), 5.53 (s, 2H), 5.03 (m, 4H), 3.41(d, 4H, J=6.2 Hz), 2.18 (s, 3H). MS (FAB) m/z 449 [M+H]⁺. Anal. calcdfor C₃₀H₂₈N₂O₂.0.35H₂O: C, 79.22; H, 6.36; N, 6.16. Found: C, 79.14; H,6.24; N, 6.43.

[0382] (d) To 3,5-dibromoaniline (2.0 g, 6.5 mmol) in CH₂Cl₂ (40 mL) wasadded diisopropylethylamine (2.27 mL, 13 mmol). The solution was cooledto 0° C. followed by addition of trifluoroacetic anhydride (1.37 mL, 9.8mmol) in CH₂Cl₂ (5 mL) over three minutes. After addition the coolingbath was removed, and DMAP (approximately 3 mgs) was added. At one hourthe solution was diluted with CH₂Cl₂ (40 mL) and washed with water andbrine and dried over sodium sulfate. The solution was concentrated andchromatographed though a short plug of silica gel eluting with 30% ethylacetate/hexanes which resulted in 2.68 g, (quantitative yield), ofN-(3,5-dibromo-4-methyl-phenyl)-2,2,2-trifluoro-acetamide an off-whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.80 (s, 3H, including NH), 2.56 (s,3H).

[0383] (e) To dry, degassed toluene (25 mL) was addedN-(3,5-dibromo-4-methyl-phenyl)-2,2,2-trifluoroacetamide (1.0 g, 2.78mmol), allyltributyltin (2.6 mL, 8.4 mmol) and Pd(PPh₃)₄ (200 mgs, 0.160mmol). After refluxing for 14 hours, most of the solvent was removed andthe solution was diluted with diethyl ether. Approximately 100 mL ofwater was added followed by DBU (1.4 mL, 0.92 mmol) which resulted in agummy precipitate. This heterogeneous solution was filtered through ashort plug of silica gel eluting with diethyl ether. After concentrationthe residue was chromotographed twice with 10 to 20% ethylacetate/hexanes resulting in 315 mg (40% yield) ofN-(3,5-diallyl-4-methyl-phenyl)-2,2,2-trifluoroacetamide as a whitesolid. ¹H NMR (300 MHz, CDCl₃) δ 7.72 (br s, 1H), 7.25 (s, 2H), 5.94 (m,2H), 5.09 (dd, J=10.2, 1.5 Hz, 2H), 4.98 (dd, J=15.4, 1.8 Hz), 3.40 (d,J=6.2 Hz), 2.18 (s, 3H).

[0384] (f) To N-(3,5-diallyl-4-methyl-phenyl)-2,2,2-trifluoroacetamide(255 mg, 0.90 mmol) in 95% ethanol (10 mL) was added 1N NaOH_((aq)) (2mL). After heating to 80° C. for 16 h, the solution was cooled to roomtemperature. After concentration the residue was diluted with ethylacetate (30 mL) and washed with water and brine and dried over sodiumsulfate. Removal of the solvent led to 160 mg (95% yield) of3,5-diallyl-4-methylaniline as an orange oil. ¹H NMR (300 MHz, CDCl₃) δ6.42 (s, 2H), 5.91 (m, 2H), 5.04 (dd, J=10.6, 1.7 Hz, 2H), 4.98 (dd,J=17.2. 1.8 Hz), 3.31 (d, J=6.3 Hz), 2.08 (s, 3H).

EXAMPLE R-2N-(3,5-Dibromo-4-methyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide

[0385]

[0386] Example R-2 was prepared in a similar manner to that describedfor R-1, except that 3,5-dibromo-4-methylaniline was used in place of3,5-diallyl-4-bromoaniline in step (c): ¹H NMR (300 MHz, DMSO-d₆) δ10.36 (s, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.20 (m, 1H), 8.14 (s, 2H),7.89 (m, 1H), 7.76 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.51 (m, 1H),7.38 (m, 1H), 5.65 (s, 2H), 2.48 (s, 3H). Anal. calc'd forC₂₄H₁₈N₂O₂Br₂.0.4H₂O: C, 54.04; H, 3.55; N, 5.25. Found: C, 53.96; H,3.50; N, 5.08.

EXAMPLE R-33-(Isoquinolin-4-ylmethoxy)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide

[0387]

[0388] Example R-3 was prepared in a similar manner to that describedfor R-1, except that2-amino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene was used inplace of 3,5-diallyl-4-bromoaniline in step (c): ¹H NMR (300 MHz,DMSO-d₆) δ 10.12 (s, 1H), 9.77 (s, 1H), 8.23 (s, 1H), 8.49 (d, 1H, J=8.2Hz), 8.39 (d, 1H, J=8.4 Hz), 8.18 (dd, 1H, J=7.8 Hz, J=7.7 Hz), 7.99(dd, 1H, J=7.4 Hz, J=7.4 Hz), 7.76 (s, 1H), 7.70 (d, 1H, J=2.2 Hz), 7.63(d, 1H, J=7.7 Hz), 7.58 (dd, 1H, J=8.6 Hz, J=2.2 Hz), 7.51 (dd, 1H,J=7.7 Hz, J=7.7 Hz), 7.38 (dd, 1H, J=8.2 Hz, J=1.9 Hz), 7.28, (d, 1H,8.6 Hz), 5.79 (s, 2H), 1.64 (s, 4H), 1.25 (s, 6H), 1.24 (s, 6H). MS(ESI) m/z 465 [M+H]⁺. Anal. calc'd for C₃₁H₃₂N₂O₂.1.0 HCl 0.8H₂O: C,72.23; H, 6.77; N, 5.43. Found: C, 72.07; H, 6.63; N, 5.43.

[0389] The intermediate2-amino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene was preparedby reduction of2-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (Kagechika,H. et al., J. Med. Chem., 31, 2182-2192 (1998)) in a similar manner tothat described in step (b) of Example J-1.

EXAMPLE R-43-(Isoquinolin-4-ylmethoxy)-N-(3-trifluoromethoxy-phenyl)-benzamide

[0390]

[0391] Example R-4 was prepared in a similar manner to that describedfor R-1, except that 3-(trifluoromethoxy)aniline was used in place of3,5-diallyl-4-bromoaniline in step (c): ¹H NMR (300 MHz, CDCl₃) δ 9.22(s, 1H), 8.55 (s, 1H), 7.99 (m, 2H), 7.73 (m, 2H), 7.65 (m, 1H), 7.60(m, 1H), 7.54 (m, 1H), 7.47 (m, 1H), 7.27-7.40 (m, 2H), 7.18 (m, 1H),6.99 (m, 1H), 5.41 (s, 2H). MS (ESI) m/z 439 [M+H]⁺. Anal. calc'd forC₂₄H₁₇F₃ N₂O₃: C, 65.75; H, 3.91; N, 6.39. Found: C, 65.58; H, 4.02; N,6.37.

EXAMPLE R-5N-(2,4-Dimethylquinolin-6-yl)-3-(isoquinolin-4-ylmethoxy)-benzamide

[0392]

[0393] Example R-5 was prepared in a similar manner to that describedfor R-1, except that 6-amino-2,4-dimethylquinoline was used in place of3,5-diallyl-4-bromoaniline in step (c): ¹H NMR (300 MHz, CDCl₃) δ 10.50(s, 1H), 9.36 (s, 1H), 8.70 (s, 1H), 8.56 (d, 1H, J=2.2 Hz), 8.20 (m,2H), 8.06 (m, 1H), 7.9 (m, 2H), 7.76 (m, 2H), 7.66 (m, 1H), 7.53 (dd,1H, J=7.8, 7.8 Hz), 7.39 (m, 1H), 7.27 (s, 1H), 5.67 (s, 2H), 2.61 (s,3H), 2.58 (s, 3H). MS (FAB) m/z 435 [M+H]⁺. Anal. calcd forC₂₇H₂₂N₄O₂.0.1H₂O: C, 74.33; H, 5.13; N, 12.84. Found: C, 79.13; H,4.97; N, 12.74.

[0394] The intermediate 6-amino-2,4-dimethylquinoline was prepared byreduction of 6-nitro-2,4-dimethylquinoline (Price, C. et al., J. Org.Chem., 12, 203 (1947)) in a similar manner to that described in step (b)of Example J-1.

EXAMPLE R-6 3-(Isoquinolin-4-ylmethoxy)-benzoic acidN′-(4-trifluoromethyl-phenyl)-hydrazide

[0395]

[0396] Example R-6 was prepared in a similar manner to that describedfor R-1, except that 4-trifluoromethylphenylhydrazine was used in placeof 3,5-diallyl-4-bromoaniline in step (c): ¹H NMR (300 MHz, CDCl₃) δ9.28 (s, 1H), 8.62 (s, 1H), 8.05 (m, 3H), 7.79(dd, 1H, J=8.36 Hz, J=8.27Hz), 7.67 (dd, 1H, J=7.98 Hz, J=8.14 Hz), 7.59 (m, 1H), 7.51-7.42 (m,4H), 7.27 (m, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 6.47 (br, 1H), 5.51 (s,2H). MS (ESI) m/z 438 [M+H]⁺. Anal. calc'd for C₂₄H₁₈F₃N₃O₂: C, 65.90;H, 4.15; N, 9.61. Found: C, 65.75; H, 4.20; N, 9.51.

EXAMPLE R-7 N-Benzyloxy-3-(isoquinolin-4-ylmethoxy)-benzamide

[0397]

[0398] Example R-2 was prepared in a similar manner to that describedfor R-1, except that O-benzylhydroxylamine was used in place of3,5-diallyl-4-bromoaniline in step (c): ¹H NMR (300 MHz, CDCl₃) δ 9.26(s, 1H), 8.59 (s, 1H), 8.57 (s, 1H), 8.05 (m, 2H), 7.78 (dd, 1H, J=8.23Hz, J=8.44 Hz), 7.67 (dd, 1H, J=7.89 Hz, J=8.16 Hz), 7.47-7.43 (m, 3H),7.42-7.32 (m, 3H), 7.24-7.16 (m, 3H), 5.47 (s, 2H), 5.05 (s, 2H). MS(ESI) r/z 385 [M+H]⁺. Anal. calc'd for C₂₄H₂₀N₂O₃: C, 74.98; H, 5.24; N,7.29. Found: C, 74.85; H, 5.31; N, 7.18.

EXAMPLE R-8 3-(Isoquinolin-4-ylmethoxy)-Benzoic Acid N′-phenyl-hydrazide

[0399]

[0400] Example R-2 was prepared in a similar manner to that describedfor R-1, except that phenyl-hydrazine was used in place of3,5-diallyl-4-bromoaniline in step (c): ¹H NMR (300 MHz, CDCl₃) δ 9.28(s, 1H), 8.62 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 7.94 (m, 1H), 7.78(m, 1H), 7.67 (m, 1H), 7.59 (m, 1H), 7.44 (m, 2H), 7.25 (m, 3H), 6.93(m, 3H), 6.38 (m, 1H), 5.50 (s, 2H). MS (ESI) m/z 370 [M+H]⁺. Anal.calcd for C₂₃H₁₉ N₃O₂.0.35H₂O: C, 73.52; H, 5.29; N, 11.18. Found: C,73.72; H, 5.36; N, 10.90.

EXAMPLE R-9N-(5,7-dimethyl[1,8]naphthydrin-2-yl)-3-(isoquinolin-4-ylmethoxy)-benzamide

[0401]

[0402] Example R-9 was prepared in a similar manner to that describedfor R-1, except that 2-amino-5,7-dimethyl[1,8]naphthydrine was used inplace of 3,5-diallyl-4-bromoaniline in step (c): ¹H NMR (300 MHz, CDCl₃)δ 9.30 (s, 1H), 8.96 (s, 1H), 8.64 (s, 2H), 8.40 (d, 1H, J=9.0 Hz), 8.08(m, 2H), 7.81 (m, 1H), 7.73 (m, 1H), 7.69 (m, 1H), 7.62 (m, 1H), 7.48(dd, 1H, J=7.8, 7.8 Hz), 7.29 (m, 1H), 7.15 (d, J=0.7 Hz), 5.55 (s, 2H),2.72 (s, 3H), 2.69 (d, 3H, J=0.7 Hz). MS (FAB) m/z 435 [M+H]⁺. Anal.calc'd for C₂₇H₂₂N₄O₂.0.1H₂O: C, 74.33; H, 5.13; N, 12.84. Found: C,79.13; H, 4.97; N, 12.74

EXAMPLE R-103-(Isoquinolin-4-ylmethoxy)-N-(1,1,3,3-tetramethyl-1,3-dihydroisobenzofuran-5-yl)-benzamide

[0403]

[0404] Example R-10 was prepared in a similar manner to that describedfor R-1, except that5-amino-1,1,3,3-tetramethyl-1,3-dihydroisobenzofuran was used in placeof 3,5-diallyl-4-bromoaniline in step (c): δ ¹H NMR (300 MHz, CDCl₃ 9.29(s, 1H), 8.63 (s, 1H), 8.06 (m, 2H), 7.90 (m, 1H), 7.79 (dd, 1H, J=8.38Hz, J=7.72 Hz), 7.68 (dd, 1H, J=8.05 Hz, J=8.08 Hz), 7.62 (m, 1H), 7.55(d, 1H, J=1.8 Hz), 7.45 (m, 2H), 7.40 (m, 1H), 7.22 (m, 1H), 7.08 (d,1H, J=8.12 Hz), 5.52 (s, 2H), 1.54 (s, 6H), 1.51 (s, 6H). MS (ESI) m/z453 [M+H]⁺. Anal. calcd for C₂₉H₂₈N₂O₃×0.4H₂O: C, 75.76; H, 6.31; N,6.09. Found: C, 75.72; H, 6.31; N, 5.94.

EXAMPLE R-11N-(3,5-Dichloro-4-pyrrolidin-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide

[0405]

[0406] Example R-11 was prepared in a similar manner to that describedfor R-1, except that ethyl 4-fluoro-3-hydroxybenzoate, prepared byconventional Fischer esterification of 4-fluoro-3-hydroxybenzoic acid,was used in place of methyl 3-hydroxybenzoate and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, in step (a), and1-(4-amino-2,6-dichlorophenyl)pyrrolidine was used in place of3,5-diallyl-4-bromoaniline in step (c): mp 163-167° C.; HPLC R_(t)=17.7min.; TLC R_(f)=0.3 (40% ethyl acetate/cyclohexane); ¹H NMR (300 MHz,DMSO-d₆) δ 10.40 (s, 1H), 8.72 (s, 1H), 8.60 (d, 1H, J=3.9 Hz),7.94-7.84 (m, 4H), 7.66-7.62 (m, 1H), 7.49-7.42 (m, 2H), 5.33 (s, 2H),3.24-3.20 (m, 4H), 1.98-1.96 (m, 4H); MS (ESI) m/z 460 [M+H]⁺. Anal.calc'd for C₂₃H₂₀Cl₂FN₃O₂: C, 60.01; H, 4.38; N, 9.13. Found: C, 60.08;H, 4.49; N, 9.02.

EXAMPLE R-124-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(pyridin-3-ylmethoxy)-benzamide

[0407]

[0408] Example R-12 was prepared in a similar manner to that describedfor R-1, except that ethyl 4-fluoro-3-hydroxybenzoate, prepared byconventional Fischer esterification of 4-fluoro-3-hydroxybenzoic acid,was used in place of methyl 3-hydroxybenzoate and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, in step (a), and1-(4-amino-2-trifluoromethylphenyl)morpholine was used in place of3,5-diallyl-4-bromoaniline in step (c): mp 160-161° C.; HPLC R_(t)=14.4min.; TLC R_(f)=0.2 (50% ethyl acetate/cyclohexane); ¹H NMR (300 MHz,DMSO-d₆) δ 10.46 (s, 1H), 8.72 (s, 1H), 8.60 (d, 1H, J=4.1 Hz), 8.14 (d,1H, J=2.4 Hz), 8.06 (dd, 1H, J=8.8, 2.4 Hz), 7.94-7.86 (m, 2H),7.69-7.61 (m, 2H), 7.50-7.41 (m, 2H), 5.34 (s, 2H), 3.71 (t, 4H, J=4.4Hz), 2.85 (t, 4H, J=4.4 Hz); MS (ESI) m/z 476 [M+H]⁺. Anal. calc'd forC₂₄H₂₁F₄N₃O₃: C, 60.63; H, 4.45; N, 8.84. Found: C, 60.84; H, 4.57; N,8.81.

EXAMPLE R-134-Fluoro-N-[4-(piperazin-1-yl)-3-trifluoromethylphenyl]-3-(pyridin-3-yl)Methoxybenzamide

[0409]

[0410] (a)4-Fluoro-N-[4-{4-(t-butoxycarbonyl)piperazin-1-yl}-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide,R-13a, was prepared in a similar manner to that described for ExampleR-1, except that ethyl 4-fluoro-3-hydroxybenzoate, prepared byconventional Fischer esterification of 4-fluoro-3-hydroxybenzoic acid,was used in place of methyl 3-hydroxybenzoate and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-₁c, in step (a), and1-(4-amino-2-trifluoromethylphenyl)-4-(t-butoxycarbonyl)piperazine wasused in place of 3,5-diallyl-4-bromoaniline in step (c).

[0411] (b) A solution of4-fluoro-N-[4-{4-(t-butoxycarbonyl)piperazin-1-yl}-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide,R-13a, (65 mg, 0.11 mmol) in methylene chloride (4 mL) was treated withtrifluoroacetic acid (1 mL). After 18 hours, the solution wasconcentrated under reduced pressure. The resultant residue was treatedwith 5% sodium bicarbonate (25 mL) and extracted with ethyl acetate(3×25 mL). The combined organic extracts were washed with water (50 mL),brine (50 mL), dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to give a tan solid (48 mg). The crude productwas purified by radial chromatography over silica gel using 5-15%methanol/chloroform with 0.1% ammonium hydroxide to give4-fluoro-N-[4-(piperazin-1-yl)-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide,R-13, as a white solid (34 mg, 63%): mp 123-131° C.; HPLC R_(t)=13.2min.; TLC R_(f)=0.3 (6% methanol/chloroform w/ 0.1% NH₄OH); ¹H NMR (300MHz, DMSO-d₆) δ 10.43 (s, 1H), 8.72 (d, 1H, J=1.6 Hz), 8.60 (dd, 1H,J=4.8, 1.5 Hz), 8.12 (d, 1H, J=2.3 Hz), 8.05-8.02 (m, 1H), 7.94-7.86 (m,2H), 7.69-7.64 (m, 1H), 7.54 (d, 1H, J=8.8 Hz), 7.49-7.41 (m, 2H), 5.33(s, 2H), 2.82-2.79 (m, 4H), 2.78-2.75 (m, 4H); MS (ESDI) m/z 475 [M+H]⁺.Anal. calc'd for C₂₄H₂₂F₄N₄O₂: C, 60.76; H, 4.67; N, 11.81. Found: C,60.66; H, 4.98; N, 11.38.

EXAMPLE R-144-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide

[0412]

[0413] Example R-14 was prepared in a similar manner to that describedfor R-1, except that ethyl 4-fluoro-3-hydroxybenzoate, prepared byconventional Fischer esterification of 4-fluoro-3-hydroxybenzoic acid,was used in place of methyl 3-hydroxybenzoate in step (a), and1-(4-amino-2-trifluoromethylphenyl)morpholine was used in place of3,5-diallyl-4-bromoaniline in step (c): mp 175-180° C.; HPLC R_(t)=15.3min.; TLC R_(f)=0.3 (1% methanol/methylene chloride); ¹H NMR (300 MHz,DMSO-d₆) δ 10.67 (s, 1H), 9.80 (s, 1H), 8.83 (s, 1H), 8.52 (d, 1H, J=8.2Hz), 8.44 (d, 1H, J=8.5 Hz), 8.23-8.17 (m, 3H), 8.12 (dd, 1H, J=8.8, 2.3Hz), 8.00 (t, 1H, J=7.4 Hz), 7.74-7.70 (m, 1H), 7.62 (d, 1H, J=8.7 Hz),7.46 (dd, 1H, J=11.0, 8.4 Hz), 5.91 (s, 2H), 3.71 (t, 4H, J=4.2 Hz),2.84 (t, 4H, J=4.2 Hz); MS (ESI) m/z 526 [M+H]⁺.

[0414] Anal. calcd for C₂₈H₂₃F₄N₃O₃.1.3 HCl: C, 58.70; H, 4.28; N, 7.33;Cl, 8.05. Found: C, 59.05; H, 4.59; N, 7.28; Cl, 8.01.

EXAMPLE R-154-Fluoro-N-(4-piperazin-1-yl-3-trifuoromethyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide

[0415]

[0416] Example R-15 was prepared in a similar manner to that describedfor R-13, except that 4-(chloromethyl)isoquinoline hydrochloride, K-1c,was used in place of 3-picolyl chloride hydrochloride in step (a): mp103-107° C.; HPLC R_(t)=14.7 min.; TLC R_(f)=0.3 (5% methanol/chloroformwith 0.1% NH₄OH); ¹H NMR (300 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.37 (s,1H), 8.68 (s, 1H), 8.23-8.17 (m, 2H), 8.14-8.13 (m, 1H), 8.06-8.02 (m,2H), 7.92-7.87 (m, 1H), 7.79-7.74 (M, 1H), 7.69-7.65 (m, 1H), 7.55 (d,1H, J=8.5 Hz), 7.42 (dd, 1H, J=11.0, 8.6 Hz), 5.72 (s, 2H), 2.80 (br. s,4H), 2.77 (br. s, 4H); MS (ESI) m/z 525 [M+H]⁺. Anal. calcd forC₂₈H₂₄F₄N₄O.0.1 hexanes (MW 533.1 g/mol): C, 64.43; H, 4.80; N, 10.51.Found: C, 64.68; H, 5.07; N, 10.16.

EXAMPLE R-164-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(quinolin-3-ylmethoxy)-benzamide

[0417]

[0418] Example R-16 was prepared in a similar manner to that describedfor R-1, except that ethyl 4-fluoro-3-hydroxybenzoate, prepared byconventional Fischer esterification of 4-fluoro-3-hydroxybenzoic acid,was used in place of methyl 3-hydroxybenzoate and3-chloromethylquinoline hydrochloride was used in place of4-(chloromethyl)isoquinoline hydrochloride, K-1c, in step (a), and1-(4-amino-2-trifluoromethylphenyl)morpholine was used in place of3,5-diallyl-4-bromoaniline in step (c): mp 81-84° C.; HPLC R_(t)=15.4min.; TLC R_(f)=0.5 (1% methanol/methylene chloride); ¹H NMR (300 MHz,DMSO-d₆) δ 10.46 (s, 1H), 9.04 (d, 1H, J=2.2 Hz), 8.49 (s, 1H), 8.14 (d,1H, J=2.4 Hz), 8.08-8.04 (m, 3H), 7.93 (dd, 1H, J=8.2, 1.8 Hz),7.83-7.78 (m, 1H), 7.70-7.60 (m, 3H), 7.46 (dd, 1H, J=11.0, 8.5 Hz),5.52 (s, 2H), 3.70 (t, 4H, J=4.3 Hz), 2.84 (t, 4H, J=4.3 Hz); MS (ESI)m/z 526 [M+H]⁺. Anal. calc'd for C₂₈H₂₃F₄N₃O₃: C, 64.00; H, 4.41; N,8.00. Found: C, 64.15; H, 4.53; N, 7.97.

EXAMPLE R-174-Fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-3-(quinolin-3-ylmethoxy)-benzamide

[0419]

[0420] Example R-17 was prepared in a similar manner to that describedfor R-13, except that 3-(chloromethyl)quinoline hydrochloride was usedin place of 3-picolyl chloride hydrochloride in step (a): mp 76-78° C.;HPLC R_(t)=14.7 min.; TLC R_(f)=0.3 (3% methanol/chloroform w/ 0.1%NH₄DH); ¹H NMR (300 MHz, DMSO-d₆) δ 10.44 (s, 1H), 9.04 (d, 1H, J=2.0Hz), 8.48 (s, 1H), 8.12 (d, 1H, J=2.1 Hz), 8.08-8.02 (m, 3H), 7.93-7.91(1,1H), 7.83-7.78 (m, 1H), 7.68-7.63 (m, 2H), 7.54 (d; 1H, J=8.9 Hz),7.46 (dd, 1H, J=11.0, 8.5 Hz), 5.52 (s, 2H), 2.81 (br. s, 4H), 2.78 (br.s, 4H); MS (ESI) m/z 525 [M+H]⁺. Anal. calc'd for C₂₈H₂₄F₄N₄O₂: C,64.12; H, 4.61; N, 10.68. Found: C, 64.53; H, 4.99; N, 10.25.

EXAMPLE R-18N-(3,5-Dichloro-4-morpholin-4-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide

[0421]

[0422] Example R-18 was prepared in a similar manner to that describedfor R-1, except that ethyl 4-fluoro-3-hydroxybenzoate, prepared byconventional Fischer esterification of 4-fluoro-3-hydroxybenzoic acid,was used in place of methyl 3-hydroxybenzoate and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, in step (a), and1-(4-amino-2,6-dichlorophenyl)morpholine was used in place of3,5-diallyl-4-bromoaniline in step (c): mp 209-211° C.; HPLC R_(t)=15.0min.; TLC R_(f)=0.3 (40% ethyl acetate/cyclohexane); ¹H NMR (300 MHz,DMSO-d₆) δ 10.41 (s, 1H), 8.71 (s, 1H), 8.58 (d, 1H, J=4.7 Hz),7.93-7.82 (m, 4H), 7.63-7.60 (m, 1H), 7.49-7.41 (m, 2H), 5.32 (s, 2H),3.70 (br. s, 4H), 3.12 (br. s, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 164.4,154.0 (d, J_(CF)=250 Hz), 149.4, 149.2, 146.0 (d, J_(CF)=11 Hz), 139.5,137.4, 136.0, 134.2, 131.8, 130.9 (d, J_(CF)=3 Hz), 123.8, 121.6 (d,J_(CF)=8 Hz), 120.4, 116.1 (d, J_(CF)=19 Hz), 115.0 (d, J_(CF)=2 Hz),68.3, 67.0, 49.4; MS (ESI) m/z 476 [M+H]⁺. Anal. calc'd forC₂₃H₂₀Cl₂FN₃O₃: C, 58.00; H, 4.23; Cl, 8.82; N, 14.89. Found: C, 57.89;H, 4.24; Cl, 14.88; N, 8.69.

EXAMPLE R-19N-(3,5-Dichloro-4-piperazin-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide

[0423]

[0424] Example R-19 was prepared in a similar manner to that describedfor R-13, except that1-(4-amino-2,6-dichlorophenyl)-4-(t-butoxycarbonyl)piperazine was usedin place of1-(4-amino-2-trifluoromethylphenyl)-4-(t-butoxycarbonyl)piperazine instep (a) mp 81-85° C.; HPLC R_(t)=11.7 min.; TLC R_(f)=0.4 (5%methanol/chloroform w/ 0.1% NH₄OH); ¹H NMR (300 MHz, DMSO-d₆) δ 10.38(s, 1H), 8.71 (d, 1H, J=1.8 Hz), 8.58 (dd, 1H, J=4.7, 1.3 Hz), 7.93-7.82(m, 4H), 7.65-7.60 (m, 1H), 7.49-7.41 (m, 2H), 5.32 (s, 2H), 3.05-3.02(m, 4H), 2.88-2.79 (m, 4H); ³C NMR (75 MHz, DMSO-d₆) δ 164.7, 152.2 (d,J_(CF)=250 Hz), 149.8, 149.5, 146.2 (d, J_(CF)=11 Hz), 140.7, 137.3,136.2, 134.4, 132.1, 131.2 (d, J_(CF)=3 Hz), 124.0, 121.8 (d, J_(CF)=8Hz), 120.7, 116.4 (d, J_(CF)=19 Hz), 115.3, 68.6, 50.8, 46.6; MS (ESI)m/z 475 [M+H]⁺. Anal. calc'd for C₂₃H₂₁Cl₂FN₄O₂: C, 58.12; H, 4.45; Cl,14.92; N, 11.79. Found: C, 57.99; H, 4.60; Cl, 14.59; N, 11.38.

EXAMPLE R-204-Fluoro-N-[4-(piperazin-1-yl)-3-trifluoromethylphenyl]-3-(pyridin-3-yl)Methoxybenzamide

[0425]

[0426] Example R-20 was prepared in a similar manner to that describedfor R-1, except that ethyl 4-fluoro-3-hydroxybenzoate, prepared byconventional Fischer esterification of 4-fluoro-3-hydroxybenzoic acid,was used in place of methyl 3-hydroxybenzoate and 3-picolyl chloridehydrochloride was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, in step (a), and1-(4-amino-2-trifluoromethylphenyl)-4-methylpiperazine was used in placeof 3,5-diallyl-4-bromoaniline in step (c): mp 61-66° C.; HPLC R_(t)=13.0min.; TLC R_(f)=0.5 (5% methanol/chloroform w/ 0.1% NH₄OH); ¹H NMR (300MHz, DMSO-d₆) δ 10.46 (s, 1H), 8.72 (s, 1H), 8.59 (d, 1H, J=4.4 Hz),8.14 (d, 1H, J=2.0 Hz), 8.05 (dd, 1H, J=8.6, 1.6 Hz), 7.94-7.86 (m, 2H),7.69-7.65 (m, 1H), 7.60 (d, 1H, J=8.8 Hz), 7.49-7.41 (m, 2H), 5.33 (s,2H), 2.92 (s, 4H), 2.88 (br. s, 4H), 2.42 (s, 3H); MS (ESI) m/z 489[M+H]⁺. Anal. calc'd for C₂₅H₂₄F₄N₄O₂ x 1.3H₂O: C, 58.66; H, 5.24; N,10.95. Found: C, 58.17; H, 4.80; N, 10.52.

EXAMPLE R-214-Fluoro-N-(4-imidazol-1-yl-3-trifluoromethyl-phenyl)-3-(pyridin-3-ylmethoxy)-benzamide

[0427]

[0428] Example R-21 was prepared in a similar manner to that describedfor R-1, except that imidazol-1-yl-trifluoromethyl-phenylamine, J-1b,was used in place of 3,5-diallyl-4-bromoaniline and4-fluoro-3-(pyridin-3-ylmethoxy)-benzoic acid, which was prepared asdescribed in R-11, was used in place of3-(isoquinolin-4-ylmethoxy)-benzoic acid, R-1b: HPLC R_(t)=12.8 min.;TLC R_(f)=0.3 (5% methanol-chloroform w/ 0.1% ammonium hydroxide); ¹HNMR (DMSO-d₆, 300 MHz) δ 10.73 (s, 1H), 8.73 (s, 1H), 8.59 (s, 1H), 8.39(d, 1H, J=2.2 Hz), 8.21 (dd, 1H, J=8.6, 2.1 Hz), 7.94-7.83 (m, 3H),7.73-7.68 (m, 1H), 7.60 (d, 1H, J=8.7 Hz), 7.51-7.40 (m, 3H), 7.10 (s,1H), 5.35 (s, 2H); MS (ESI) m/z 457 (M+H)⁺. Anal. calcd forC₂₃H₁₆F₄N₄O₂: C, 60.53; H, 3.53; N, 12.28. Found: C, 60.37; H, 3.62; N,12.21.

EXAMPLE R-224-Fluoro-N-(4-pyrazol-1-yl-3-trifluoromethyl-phenyl)-3-(pyridin-3-ylmethoxy)-benzamide

[0429]

[0430] Example R-22 was prepared in a similar manner to that describedfor R-1, except that pyrazol-1-yl-trifluoromethyl-phenylamine was usedin place of 3,5-diallyl-4-bromoaniline and4-fluoro-3-(pyridin-3-ylmethoxy)-benzoic acid, which was prepared asdescribed in R-11, was used in place of3-(isoquinolin-4-ylmethoxy)-benzoic acid, R-1b: HPLC R_(t) 13.9 min.;TLC R_(f) 0.2 (2% methanol-chloroform w/ 0.11% ammonium hydroxide); ¹HNMR (DMSO-d₆, 300 MHz) δ 10.72 (s, 1H), 8.72 (d, 1H, J=1.8 Hz), 8.60(dd, 1H, J=4.6, 1.2 Hz), 8.38 (d, 1H, J=2.3 Hz), 8.21 (dd, 1H, J=8.7,2.3 Hz), 8.02 (d, 1H, J=2.2 Hz), 7.95-7.89 (m, 2H), 7.74-7.69 (m, 2H),7.68 (d, 1H, J=8.7 Hz), 7.51-7.44 (m, 2H), 6.52-6.51 (m, 1H), 5.35 (s,2H); MS (ESI) m/z 457 (M+H)⁺. Anal. calcd for C₂₃H₁₆F₄N₄O₂: C, 60.53; H,3.53; N, 12.28. Found: C, 60.39; H, 3.64; N, 12.19.

EXAMPLE R-234-Fluoro-3-(pyridin-3-ylmethoxy)-N-(4-[1,2,4]triazol-1-yl-3-trifluoromethyl-phenyl)-benzamide

[0431]

[0432] Example R-23 was prepared in a similar manner to that describedfor R-1, except that [1,2,4]triazol-1-yl-trifluoromethyl-phenylamine wasused in place of 3,5-diallyl-4-bromoaniline and4-fluoro-3-(pyridin-3-ylmethoxy)-benzoic acid, which was prepared asdescribed in R-11, was used in place of3-(isoquinolin-4-ylmethoxy)-benzoic acid, R-1b: HPLC R_(t) 12.4 min.;TLC R_(f) 0.3 (5% methanol-chloroform w/ 0.1% ammonium hydroxide); ¹HNMR (DMSO-d₆, 300 MHz) δ 10.79 (s, 1H), 8.89 (s, 1H), 8.73 (d, 1H, J=1.7Hz), 8.60 (dd, 1H, J=4.8, 1.8 Hz), 8.44 (d, 1H, J=2.3 Hz), 8.28-8.24 (m,2H), 7.96-7.90 (m, 2H), 7.74-7.69 (m, 2H), 7.52-7.45 (m, 2H), 5.35 (s,2H); MS (ESI) m/z 458 (M+H)⁺. Anal. calcd for C₂₂H₁₅F₄N₅O₂: C, 56.65; H,3.46; N, 15.02. Found: C, 56.53; H, 3.44; N, 14.96.

EXAMPLE R-24N-(3,5-Dichloro-4-imidazol-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide

[0433]

[0434] Example R-24 was prepared in a similar manner to that describedfor R-1, except that 3,5-dichloro-4-imidazol-1-yl-phenylamine was usedin place of 3,5-diallyl-4-bromoaniline and4-fluoro-3-(pyridin-3-ylmethoxy)-benzoic acid, which was prepared asdescribed in R-11, was used in place of3-(isoquinolin-4-ylmethoxy)-benzoic acid, R-1b: HPLC R_(t) 13.0 min.;TLC R_(f) 0.7 (5% methanol-dichloromethane); ¹H NMR (DMSO-d₆, 300 MHz) δ10.65 (s, 1H), 8.89 (s, 1H), 8.72 (d, 1H, J=1.9 Hz), 8.60 (dd, 1H,J=4.8, 1.6 Hz), 8.11 (s, 2H), 7.95-7.91 (m, 1H), 7.88 (dd, 1H, J=8.2,2.0 Hz), 7.81 (s, 1H), 7.71-7.66 (m, 1H), 7.51-7.44 (m, 2H), 7.33 (s,1H), 7.13 (s, 1H), 5.34 (s, 2H); ¹³C NMR (DMSO-d₆, 75 MHz) δ 165.2,154.6 (d, J_(CF)=251.1 Hz), 149.9, 149.6, 146.4(d, J_(CF)=11.1 Hz),141.2, 138.4, 136.3, 133.1, 132.2, 130.9 (d, J_(CF)=3.5 Hz), 129.2,128.3, 124.1, 122.0 (d, J_(CF)=7.6 Hz), 121.3, 119.9, 116.6 (d,J_(CF)=18.7 Hz), 115.6 (d, J_(CF)=1.7 Hz), 68.8; MS (ESI) m/z 457(M+H)⁺. Anal. calcd for C₂₂H₁₅Cl₂FN₄O₂: C, 57.78; H, 3.31; N, 12.25; Cl,15.51. Found: C, 57.38; H, 3.52; N, 11.90; Cl, 16.40.

EXAMPLE R-253-(5-Bromo-pyridin-3-ylmethoxy)-4-fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamide

[0435]

[0436] (a) (5-Bromo-pyridin-3-yl)-methanol hydrochloride, R-25a, wasprepared according to the procedure described in J. Med. Chem., 1997,40, 2866-2875: HPLC R_(t) 3.9 min.; TLC R_(f) 0.2 (free base; 40% ethylacetate-cyclohexane); ¹H NMR (DMSO-d₆, 300 MHz) δ 8.70 (d, 1H, J=2.2Hz), 8.58-8.57 (m, 1H), 8.11 (t, 1H, J=2.0 Hz), 4.57 (s, 2H); ¹³C NMR(DMSO-d₆, 75 MHz) δ 144.1, 141.9, 140.2, 120.8, 59.9; MS (ESI) m/z188/190 (M+H)⁺.

[0437] (b) To a solution of (5-bromo-pyridin-3-yl)-methanolhydrochloride, R-25a, (1.9 g, 8.5 mmol, 1.0 eq) was added thionylchloride (6 mL, 85 mmol, 10 eq). The amber solution was warmed to 70° C.for 2 h. The crude product was cooled to room temperature, diluted withtoluene (50 mL) and concentrated under reduced pressure to give3-bromo-5-chloromethyl-pyridine hydrochloride, R-25b, as a tan solid:HPLC R_(t) 10.1 min.; ¹H NMR (DMSO-d₆, 300 MHz) δ 8.72 (d, 1H, J=2.2Hz), 8.68 (d, 1H, J=1.7 Hz), 8.21 (t, 1H, J=2.0 Hz), 4.43 (s, 2H); ¹³CNMR (DMSO-d₆, 75 MHz) δ 149.8, 148.0, 140.2, 136.4, 120.5, 42.3; MS(ESI) m/z 206/208 (M+H)⁺.

[0438] (c)4-[({1-[3-(5-Bromo-pyridin-3-ylmethoxy)-4-fluoro-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, R-25c, was prepared in a similar manner to thatdescribed for R-1a, except that 3-bromo-5-chloromethyl-pyridinehydrochloride, R-25b, was used in place of 4-(chloromethyl)isoquinolinehydrochloride, K-1c, and4-({[1-(4-fluoro-3-hydroxy-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, DD-1a, was used in place of 3-hydroxybenzoate:HPLC R_(t) 19.2 min.; TLC R_(f) 0.3 (2% methanol-dichloromethane); ¹HNMR (DMSO-d₆, 300 MHz) δ 10.44 (s, 1H), 8.74 (d, 1H, J=2.2 Hz), 8.72 (d,1H, J=1.7 Hz), 8.21 (t, 1H, J=2.0 Hz), 8.14 (d, 1H, J=2.4 Hz), 8.04 (dd,1H, J=8.6, 2.4 Hz), 7.86 (dd, 1H, J=8.2, 2.0 Hz), 7.71-7.66 (m, 1H),7.60 (d, 1H, J=8.8 Hz), 7.46 (dd, 1H, J=11.0, 8.5 Hz), 5.34 (s, 2H),3.44 (br. s, 4H), 2.80 (t, 4H, J=4.7 Hz), 1.44 (s, 9H); MS (ESI) m/z653/655 (M+H)⁺.

[0439] (d)3-(5-Bromo-pyridin-3-ylmethoxy)-4-fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride, R-25, was prepared in the manner similar to thatdescribed in example AA-1, step (i), except4-[({1-[3-(5-bromo-pyridin-3-ylmethoxy)-4-fluoro-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, R-25c, was used in place of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1 h: HPLC R_(t) 13.1 min.; ¹H NMR (DMSO-d₆,300 MHz) δ 10.59 (s, 1H), 9.05 (br. s, 2H), 8.74-8.72 (m, 2H), 8.20 (d,2H, J=1.9 Hz), 8.12 (d, 1H, J=8.7 Hz), 7.92 (d, 1H, 3=7.9 Hz), 7.71-7.68(m, 1H), 7.56 (d, 1H, J=8.7 Hz), 7.44 (dd, 1H, J=11.0, 8.6 Hz), 5.36 (s,2H), 3.17 (br. s, 4H), 3.07 (br. s, 4H); MS (ESI) m/z 553/555 (M+H)⁺.Anal. calcd for C₂₄H₂₁BrF₄N₄O₂x 2.0 HClx0.6H₂O: C, 45.24; H, 3.83; N,8.79; Br, 12.54; Cl, 11.13. Found: C, 45.20; H, 3.94; N, 8.50; Br,12.18; Cl, 10.81.

EXAMPLE S-1 3-(2-Isoquinolin-4-yl-ethyl)-N-phenyl-benzamide

[0440]

[0441] (a) 4-Bromoisoquinoline (1.0 g, 4.8 mmol),dichlorobis(triphenylphosphine)palladium (20.4 mg, 0.029 mmol), copperiodide (1.5 mg, 0.008 mmol), trimethylsilylacetylene (707 mg, 7.2 mmol)and triethylamine (20 ml) were heated in a sealed tube at 65° C. for 16h. After concentration the residue was diluted with ethyl acetate,washed with brine, dried over sodium sulfate, filtered and concentratedto dryness. The crude residue was purified on silica gel using agradient of 10% to 20% ethyl acetate in hexanes as eluant to obtain 1.01g (93%) of 4-(trimethyl-silanylethynyl)-isoquinoline, S-1a, as a yellowliquid: ¹H NMR (300 MHz, CDCl₃) δ 9.18 (s, 1H), 8.70 (s, 1H), 8.34 (m,1H), 8.14 (m, 1H), 7.78 (m, 1H), 7.65 (m, 1H), 0.35 (s, 9H).

[0442] (b) To a solution of NaOH (0.23 g, 5.78 mmol) in methanol wasadded 1.0 g (4.44 mmol) 4-(trimethyl-silanylethynyl)-isoquinoline, S-1a.After stirring for 2 h at room temperature the methanol was removedfollowed by addition of ethyl acetate. The organic solution was washedwith water, brine and dried over sodium sulfate. Removal of solvent ledto 0.65 g (96%) of 4-ethynyl-isoquinotine, S-1b: ¹H NMR (300 MHz, CDCl₃)δ 9.22 (s, 1H), 8.74 (s, 1H), 8.27 (m, 1H), 7.99 (m, 1H), 7.80 (m, 1H),7.67 (m, 1H), 3.55 (s, 1H).

[0443] (c) 4-Ethynyl-isoquinoline, S-1b, (0.64 g, 4.18 mmol), ethyl3-iodobenzoate (1.15 g, 4.18 mmol),dichlorobis(triphenylphosphine)palladium (7.02 mg, 0.010 mmol) andcopper iodide (0.4 mg, 0.002 mmol) in triethylamine (20 ml) were stirredat room temperature for 14 h. The mixture was filtered through celite,and the filtrate was concentrated to remove triethylamine. To thisresidue was added ethyl acetate, and this solution was washed withbrine, dried over sodium sulfate, and concentrated to dryness. The cruderesidue was purified on silica gel using a gradient 0% to 5% ethylacetate in dichloromethane as eluant to obtain 1.1 g (87%) of ethyl3-(isoquinolin-4-ylethynyl)benzoate, S-1c, as a semisolid: ¹H NMR (300MHz, CDCl₃) δ 9.23 (brs, 1H), 8.80 (br s, 1H), 8.32 (m, 2H), 8.07 (m,1H), 8.03 (m, 1H), 7.84 (m, 2H), 7.69 (m, 2H), 7.50 (dd, 1H, J=7.4 Hz),4.43 (q, 2H, J=7.1 Hz), 1.44 (t, 3H, J=7.1 Hz).

[0444] (d) Ethyl 3-(isoquinolin-4-ylethynyl)benzoate, S-1c, (1.1 g, 3.64mmol) and 10% Pd/C (0.5 g) in ethanol (20 ml) were stirred under one atmof hydrogen at room temperature for 16 h. The solution was filteredthrough celite, and the filtrate was concentrated leaving 1.02 g (91.6%)of ethyl 3-(isoquinolin-4-ylethyl)benzoate, S-1d, as a liquid: ¹H NMR(300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.32 (s, 1H), 8.01 (m, 2H), 7.91 (m,2H), 7.75 (m, 1H), 7.62 (m, 1H), 7.34 (m, 2H), 4.39 (q, 2H J=7.1 Hz),3.35 (m, 2H), 3.10 (m, 2H), 1.40 (t, 3H, J=7.1 Hz).

[0445] (e) To a stirred solution of ethyl3-(isoquinolin-4-ylethyl)benzoate, S-1d, (1.02 g, 3.3 mmol) in methanol(20 ml) was added 1N NaOH (3.63 ml, 3.63 mmol). After refluxing for 4 h,the methanol was removed. The solution was diluted with water and uponacidification to pH 3 a white precipitate formed which was subsequentlyfiltered and dried under high vacuum to obtain 0.92 g (100%) of3-(2-isoquinolin-4-yl-ethyl)-benzoic acid, S-1e: ¹H NMR (300 MHz, CDCl₃)δ 9.75 (s, 1H), 8.54 (m, 3H), 8.21 (m, 1H), 8.02 (m, 1H), 7.89 (br s,1H), 7.80 (m, 1H), 7.57 (m, 1H), 7.43 (dd, 1H, J=7.7 Hz), 3.52 (m, 2H),3.11 (m, 2H).

[0446] (f) To a stirred solution of 3-(2-isoquinolin-4-yl-ethyl)-benzoicacid, S-1e, (0.2 g, 0.64 mmol), N-hydroxybenzotriazole (0.11 g, 0.70mmol), and aniline (0.06 g, 0.65 mmol) in DMF (10 ml) was added1-ethyl-3-(3′-dimethylaminopropyl)carbodiimideHCl (0.148 g, 0.77 mmol)at 0° C. After stirring for 16 hrs. the DMF was removed, and ethylacetate was added. This solution was washed with sat. NaHCO₃, brine anddried over sodium sulfate. The crude residue was purified on silica gelusing a gradient of 0% to 30% ethyl acetate in dichloromethane as eluantto obtain 0.18 g (80%) of3-(2-isoquinolin-4-yl-ethyl)-N-phenyl-benzamide, S-1, as a solid: ¹H NMR(300 MHz, CDCl₃) δ 9.16 (s, 1H), 8.30 (s, 1H), 8.04-7.99 (m, 2H), 7.76(dd, 1H, J=8.34 Hz, J=8.37 Hz), 7.71-7.69 (m, 1H), 7.67-7.60 (m, 5H),7.44-7.35 (m, 4H), 7.19-7.12 (m, 1H), 3.39-3.34 (m, 2H), 3.16-3.11 (m,2H). MS (ESI) m/z 353 [M+H]⁺. Anal. calc'd for C₂₄H₂₀N₂O.0.2H₂O: C,80.96; H, 5.78; N, 7.87. Found: C, 80.88; H, 5.85; N, 8.03.

EXAMPLE S-23-(2-Isoquinolin-4-yl-ethyl)-N-(3,3,5-trimethyl-cyclohexyl)-benzamide

[0447]

[0448] Example S-2 was prepared in a similar manner to that describedfor S-1, except that (±)-cis/trans-3,3,5-trimethylcyclohexylamine wasused in place of aniline in step (f): ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s,1H), 8.31 (s, 1H), 8.01 (m, 2H), 7.75 (dd, 1H, J=8.4 Hz, J=8.4 Hz), 7.63(dd, 1H, J=8.0 Hz, J=8.0 Hz), 7.56 (m, 1H), 7.52 (m, 1H), 7.36-7.28 (m,2H), 5.72 (d, 1H, J=7.9 Hz), 4.16 (m, 1H), 3.37 (m, 2H), 3.10 (m, 2H),2.90 (m, 1H), 1.78 (m, 2H), 1.38 (m, 1H), 1.03 (s, 3H), 0.97 (s, 3H),0.92 (d, 3H, J=6.5 Hz), 0.84-0.64 (m, 3H). MS (ESI) m/z 401 [M+H]⁺.Anal. calc'd for C₂₇H₃₂N₂O.0.1H₂O: C, 80.60; H, 8.07; N, 6.96. Found: C,80.40; H, 8.20; N, 6.85.

EXAMPLE S-3N-(4-Isopropyl-3-methyl-phenyl)-3-(2-isoquinolin-4-yl-ethyl)-benzamide

[0449]

[0450] Example S-3 was prepared in a similar manner to that describedfor S-1, except that 4-isopropyl-3-methylaniline was used in place ofaniline in step (f): ¹H NMR (300 MHz, CDCl₃) δ 9.16 (s, 1H), 8.31 (s,1H), 8.04-7.99 (m, 2H), 7.76 (dd, 1H, J=8.3 Hz, J=8.4 Hz), 7.68-7.61 (m,4H), 7.45-7.34 (m, 4H), 7.23 (m, 1H), 3.39-3.34 (m, 2H), 3.15-3.10 (m,3H), 2.36 (s, 3H), 1.23 (d, 6H, J=6.9 Hz). MS (ESI) m/z 409 [M+H]⁺.Anal. calc'd for C₂₈H₂₈N₂O.0.2H₂O: C, 81.60; H, 6.95; N, 6.80. Found: C,81.51; H, 6.99; N, 6.85.

EXAMPLE S-43-(2-Isoquinolin-4-yl-ethyl)-N-(2-methyl-quinolin-6-yl)-benzamide

[0451]

[0452] Example S-4 was prepared in a similar manner to that describedfor S-1, except that 6-amino-2-methylquinoline was used in place ofaniline in step (f): ¹H NMR (300 MHz, CDCl₃) δ 9.16 (s, 1H), 8.44 (d,1H, J=2.4 Hz), 8.29 (s, 1H), 8.07-7.97 (m, 5H), 7.79-7.71 (m, 2H),7.68-7.61 (m, 3H), 7.46-7.38 (m, 2H), 7.29 (d, 1H, J=8.4 Hz), 3.40-3.35(m, 2H), 3.17-3.10 (m, 2H), 2.74 (s, 3H). MS (ESI) m/z 418 [M+H]⁺. Anal.calc'd for C₂₈H₂₃N₃O.0.4H₂O: C, 79.18; H, 5.65; N, 9.89. Found: C,79.01; H, 5.86; N, 9.67.

EXAMPLE S-5N-(3,5-Dibromo-4-methyl-phenyl)-3-(2-isoquinolin-4-yl-ethyl)-benzamide

[0453]

[0454] Example S-5 was prepared in a similar manner to that describedfor S-1, except that 3,5-dibromo-4-methylaniline was used in place ofaniline in step (f): ¹H NMR (300 MHz, CDCl₃) δ 9.16 (s, 1H), 8.25 (s,1H), 8.01 (m, 2H), 7.88 (s, 2H), 7.76 (dd, 1H, J=8.16 Hz, J=8.51 Hz),7.68-7.61 (m, 3H), 7.52 (m, 1H), 7.43-7.35 (m, 2H), 3.41-3.32 (m, 2H),3.15-3.09 (m, 2H), 2.54 (s, 3H). MS (ESI) m/z 525 [M+H]⁺. Anal. calcdfor C₂₅H₂₀N₂OBr₂* C₂F₃ OOH: C, 50.80; H, 3.32; N, 4.39. Found: C, 50.84;H, 3.40; N, 4.51.

EXAMPLE S-6 N-(4,6-Dimethyl-pyridin-2yl)-3(2isoquinolin-4-yl-ethyl)-benzamide

[0455]

[0456] Example S-6 was prepared in a similar manner to that describedfor S-1, except that 2-amino-4,6-dimethylpyridine was used in place ofaniline in step (f): ¹H NMR (300 MHz, CDCl₃) δ 9.16 (s, 1H), 8.40 (m,1H), 8.35 (s, 1H), 8.03 (m, 3H), 7.80-7.73 (m, 3H), 7.63 (dd, 1H, J=8.04Hz, J=7.9 Hz), 7.44-7.36 (m, 2H), 6.79 (s, 1H), 3.39-3.34 (m, 2H),3.16-3.10 (m, 2H), 2.45 (s, 3H), 2.37 (s, 3H). MS (ESI) m/z 382 [M+H]⁺.Anal. calcd for C₂₅H₂₃N₃O.2C₂F₃ OOH.0.5H₂O: C, 56.31; H, 4.24; N, 6.79.Found: C, 56.16; H, 4.17; N, 6.75.

EXAMPLE S-72-Chloro-4-fluoro-N.(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide

[0457]

[0458] Example S-7 was prepared in a similar manner to that describedfor S-1, except that ethyl 2-chloro-4-fluoro-5-bromobenzoate was used inplace of ethyl 3-iodobenzoate in step (c), and4-isopropyl-3-methylaniline was used in place of aniline in step (f): ¹HNMR (300 MHz, CDCl₃) δ 9.15 (s, 1H), 8.27 (s, 1H), 8.03(m, 2H),7.81-7.76 (m, 2H), 7.64 (dd, 1H, J=7.17 Hz, J=7.11 Hz), 7.33 (d, 1H,J=7.91 Hz), 7.44-7.41 (m, 2H), 7.21-7.16 (m, 2H), 3.34-3.32 (m, 2H),3.19-3.05 (m, 3H), 2.36 (s, 3H), 1.23(d, 6H, J=6.85 Hz). MS (ESI) m/z461 [M]⁺. Anal. calcd for C₂₈H₂₆ClFN₂O: C, 72.95; H, 5.69; N, 6.08.Found: C, 72.70; H, 5.76; N, 6.03.

EXAMPLE S-82,4-Difluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide

[0459]

[0460] Example S-8 was prepared in a similar manner to that describedfor S-1, except that methyl 2,4-difluoro-5-bromobenzoate was used inplace of ethyl 3-iodobenzoate in step (c), and4-isopropyl-3-methylaniline was used in place of aniline in step (f): ¹HNMR (300 MHz, CDCl₃) δ 9.15 (s, 1H), 8.32 (s, 1H), 8.25 (m, 1H),8.10-7.99 (m, 3H), 7.78 (dd, 1H, J=7.3 Hz, J=8.4 Hz), 7.64 (dd, 1H,J=8.4 Hz, J=8.0 Hz), 7.47-7.40 (m, 2H), 7.24 (m, 1H), 6.92 (dd, 1H,J=11.8 Hz, J=11.8 Hz), 3.35-3.30 (m, 2H), 3.17-3.07 (m, 3H), 2.36 (s,3H), 1.24 (d, 6H, J=6.9 Hz). MS (ESI) m/z 445 [M]⁺. Anal. calc'd forC₂₈H₂₆F₃N₂O: C, 75.66; H, 5.90; N, 6.30. Found: C, 75.42; H, 5.92; N,6.22.

EXAMPLE T-12-Fluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide

[0461]

[0462] (a) 5-Bromo-2-fluoro-N-(4-isopropyl-3-methyl-phenyl)-benzamide,T-1a, was prepared from 4-isopropyl-3-methyl aniline and4-bromo-2-fluorobenzoic acid in a manner similar to that described for3-(2-isoquinolin-4-yl-ethyl)-N-phenyl-benzamide in Example S-1, step(f), except that benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate was used in place of1-ethyl-3-(3′-dimethylaminopropyl)carbodiimideHCl andN-hydroxybenzotriazole: ¹H NMR (300 MHz, CDCl₃) δ 8.29 (dd, J=10.5, 7.9Hz, 1H), 8.24 (br s, 1H), 7.60 (m, 1H), 7.42 (m, 2H), 7.24 (d, J=8.4 Hz,1H), 7.08 (dd, J=11.4, 8.7 Hz, 1H), 3.12 (septet, J=6.8 Hz, 1H), 2.36(s, 3H), 1.27 (d, J=6.8 Hz, 6H).

[0463] (b)2-Fluoro-N-(4-isopropyl-3-methyl-phenyl)-5-isoquinolin-4-ylethynyl-benzamide,T-1b, was prepared in the manner similar to that described in ExampleS-1, step (c) for ethyl 3-isoquinolin-4-ylethynyl-benzoate, S-1c, exceptthat 5-bromo-2-fluoro-N-(4-isopropyl-3-methyl-phenyl)benzamide, T-1a,was used in place of ethyl 3-iodobenzoate. ¹H NMR (300 MHz, CDCl₃) δ9.23 (s, 1H), 9.08 (s, 1H), 8.47 (dd, J=7.5, 2.2 Hz, 1H), 8.34 (m, 2H),8.02 (d, J=8.1 Hz, 1H), 7.84 (m, 1H), 7.78 (m, 1H), 7.69 (m, 1H), 7.48(m, 2H), 7.25 (m, 2H), 3.14 (septet, J=6.8 Hz, 1H), 2.38 (s, 3H), 1.24(d, J=6.8 Hz, 6H).

[0464] (c)2-Fluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide,T-1, was prepared in a manner similar to that described in Example S— l,step (d) for 3-(2-isoquinolin-4-yl-ethyl)-benzoic acid ethyl ester,S-1d: ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.37 (m, 1H), 8.29 (s, 1H)8.05-7.99 (m, 3H), 7.77 (dd, 1H, J=8.3 Hz), 7.63 (dd, 1H, J=8.1 Hz),7.49-7.45 (m, 2H), 7.23 (m, 2H), 7.07 (dd, 1H, J=12 Hz), 3.37-3.32 (m,2H), 3.18-3.07 (m, 3H), 2.37 (s, 3H), 1.23 (d, 6H, J=6.9 Hz). MS (ESI)m/z 427 [M+H]⁺. Anal. calc'd for C₂₈H₂₇FN₂O: C, 78.85; H, 6.38; N, 6.57.Found: C, 78.91; H, 6.35; N, 6.39.

EXAMPLE U-1 N-(2-Methyl-quinolin-6yl)-3-(2-pyridin-3-yl-ethyl)BenzamideHydrochloride

[0465]

[0466] (a) A solution of 2-methyl-quinolin-6-ylamine (Maybridge, 836 mg,5.29 mmol, 1.0 eq) and triethylamine (0.74 mL, 5.29 mmol, 1.0 eq) indichloromethane (100 mL) was cooled to 0° C. and treated with3-chloromethyl-benzoyl chloride (Aldrich, 0.75 mL, 5.29 mmol, 1.0 eq). Atan slurry forms within 30 minutes. After 1.0 hour, TLC (4%methanol/chloroform) gave no 2-methyl-quinolin-6-ylamine (R_(f) 0.4),and a new spot with R_(f) 0.6. A 5% sodium bicarbonate solution (100 mL)was added to the reaction mixture, and the aqueous layer was extractedwith 10% isopropanol/chloroform (3×100 mL) to give a yellow solid (1.31g). The product was washed with diethyl ether to give3-chloromethyl-N-(2-methyl-quinolin-6-yl)-benzamide, U-1a, as a yellowsolid (1.28 g, 78%): HPLC R_(t)=12.8 min.; TLC R_(f)=0.6 (4%methanol/chloroform); ¹H NMR (300 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.46(d, 1H, J=2.2 Hz), 8.22 (d, 1H, J=8.4 Hz), 8.07-7.90 (m, 4H), 7.70-7.69(m, 1H), 7.58 (t, 1H, J=7.6 Hz), 7.40 (d, 1H, J=8.4 Hz), 4.88 (s, 2H),2.65 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) □ 165.8, 158.0, 144.2, 138.4,136.6, 136.5, 135.4, 132.5, 129.3, 128.4, 127.9, 126.7, 124.6, 123.0,117.0, 116.8, 46.0, 24.7; MS (ESI) m/z 311 [M+H]⁺.

[0467] (b) A solution of3-chloromethyl-N-(2-methyl-quinolin-6-yl)-benzamide, U-1a, (500 mg, 1.6mmol, 1.0 eq) in acetone (250 mL) was heated to 55° C. and treated withsodium iodide (3.2 g, 150 mmol, 13 eq). After 2.0 h, no startingmaterial was detected by HPLC, and the resulting yellow solution wasconcentrated under reduced pressure. The resulting residue was treatedwith water (100 mL) and the aqueous layer was extracted with chloroform(3×100 mL). The combined organic extracts were washed with Na₂S₂O₃ (100mL), brine (100 mL), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give3-iodomethyl-N-(2-methyl-quinolin-6-yl)-benzamide, U-1b, as a yellowsolid (615 mg, 96%): HPLC R_(t)=13.6 min.; TLC R_(f)=0.5 (5%methanol/chloroform); ¹H NMR (300 MHz, DMSO-d₆) δ 10.52 (s, 1H), 8.44(d, 1H, J=2.1 Hz), 8.22 (d, 1H, J=8.5 Hz), 8.12-7.88 (m, 4H), 7.68-7.66(m, 1H), 7.51 (t, 1H, J=7.7 Hz), 7.40 (d, 1H, J=8.5 Hz), 4.72 (s, 2H),2.65 (s, 3H); MS (ESI) m/z 403 [M+H]⁺.

[0468] (c) A solution of3-iodomethyl-N-(2-methyl-quinolin-6-yl)-benzamide, U-1b, (565 mg, 1.4mg, 1.0 eq) in acetone (140 mL) was treated with triphenylphosphine(1.80 g, 7.0 mmol, 5.0 eq) and heated to 55° C. to give a yellowsolution. After 18 hours, the resulting slurry gave no starting material(R_(f) 0.5) by TLC (5% methanol/chloroform), only product with R_(f)0.0-0.3. The solvent was removed under reduced pressure and theresulting solid was washed with methyl-tert-butyl ether (4×25 mL) togiveN-(2-methyl-quinolin-6-yl)-3-[(triphenylphosphanyl)-methyl]-benzamideiodide, U-1c, as a yellow solid (809 mg, 87%): HPLC R_(t)=14.4 min.; TLCR_(f)=0.0-0.3 (5% methanol/chloroform); ¹H NMR (500 MHz, DMSO-d₆) δ10.24 (s, 1H), 8.18 (d, 1H, J=1.1 Hz), 8.02 (d, 1H, J=8.5 Hz), 7.80 (d,1H, J=7.8 Hz), 7.75-7.71 (m, 5H), 7.60-7.45 (m, 13H), 7.27-7.21 (m, 2H),7.00 (d, 1H, J=7.7 Hz), 5.10 (d, 2H, J=15.7 Hz), 2.46 (s, 3H); MS (ESI)m/z 537 [M+H)⁺.

[0469] (d) A solution ofN-(2-methyl-quinolin-6-yl)-3-[(triphenylphosphanyl)-methyl]-benzamideiodide, U-1c, (600 mg, 0.90 mmol, 1.0 eq) in THF (20 mL) was cooled to−78° C. and treated with a 1.0 M solution of sodiumbis(trimethylsilyl)amide in THF (1.9 mL, 1.9 mmol, 2.1 eq) to give adark orange solution. The solution was aged for 30 min at −78° C., thentreated with pyridine-3-carbaldehyde (93 μL, 0.99 mmol, 1.1 eq). Theorange mixture was allowed to gradually warm to −30° C. over 2 h,removed from the cold bath and stirred at room temperature for 1.0 hour.The reaction was quenched with water (100 mL) and the aqueous layer wasextracted with chloroform (3×100 mL). The combined organic extracts werewashed with brine (100 mL), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give a black oil (700 mg). Thecrude product was purified by radial chromatography over silica gelusing 3-4% methanol/chloroform to givetrans-N-(2-methyl-quinolin-6-yl)-3-(2-pyridin-3-yl-vinyl)-benzamide,U-1d, as a white solid (59 mg, 18%): HPLC R_(t)=12.3 min.; TLC R_(f)=0.4(5% methanol/chloroform); ¹H NMR (500 MHz, DMSO-d₆) δ 10.50 (s, 1H),8.45-8.41 (m, 3H), 8.20 (d, 1H, J=8.4 Hz), 7.96 (dd, 1H, J=2.3, 9.1 Hz),7.91-7.88 (m, 3H), 7.63-7.60 (m, 1H), 7.47 (t, 1H, J=7.5 Hz), 7.41-7.39(m, 2H), 7.31 (dd, 1H, J=4.8, 8.0 Hz), 6.92 (d, 1H, J=12.3 Hz), 6.78 (d,1H, J=12.3 Hz), 2.64 (s, 3H); MS (ESI) m/z 366 [M+H]⁺. Anal. calc'd forC₂₄H₁₉N₃O.0.2H₂O: C, 78.11; H, 5.30; N, 11.39. Found: C, 78.08; H, 5.38;N, 11.25.

[0470] (d) A solution oftrans-N-(2-methyl-quinolin-6-yl)-3-(2-pyridin-3-yl-vinyl)-benzamide,U-1d, (44 mg, 0.12 mmol) in methanol (3 mL) was shaken vigorously underhydrogen (40 psi) with 5% palladium on carbon for 24 h. The catalyst wasfiltered off, and the filtrate was concentrated under reduced pressureto give a clear oil (50 mg). The crude product was purified by radialchromatography over silica gel using 2-4% methanol/dichloromethane togive a clear oil. The oil was dissolved in ethanol and treated with 0.1mL concentrated hydrochloric acid. The solvent was removed under reducedpressure to giveN-(2-methyl-quinolin-6-yl)-3-(2-pyridin-3-yl-ethyl)-benzamidehydrochloride, U-1, as a white solid (35 mg, 66%): HPLC R_(t) 12.4 min.;¹H NMR (500 MHz, DMSO-d₆ w/ D₂O) δ (s, 1H), 8.96 (d, 1H, J=8.7 Hz),8.82-8.81 (m, 2H), 8.74 (d, 1H, J=5.4 Hz), 8.46 (d, 1H, J=8.0 Hz), 8.38(dd, 1H, J=1.8, 9.2 Hz), 8.23 (d, 1H, J=9.2 Hz), 7.98-7.89 (m, 4H),7.53-7.52 (m, 2H), 3.21 (t, 2H, J=7.8 Hz), 3.11 (t, 2H, J=7.7 Hz), 2.93(s, 3H); ¹³C NMR (75 MHz, DMSO-d₆ w/ D₂O) δ 166.9, 156.6, 146.1, 144.8,141.8, 141.3, 141.1, 140.2, 139.1, 135.0, 144.4, 132.8, 129.1, 128.5,128.2, 127.6, 127.0, 126.1, 124.3, 121.4, 117, 35.7, 33.5, 20.9; MS(ESI) m/z 368 [M+H]⁺. Anal. calc'd for C₂₄H₂₁N₃O.2HCl 0.3H₂O: C, 64.66;H, 5.34; N, 9.43; Cl, 15.91. Found: C, 64.63; H, 5.40; N, 9.10; Cl,15.62.

EXAMPLE U-2N-(4-Isopropyl-3-methyl-phenyl)-3-(2-pyridin-3-yl-ethyl)-benzamide

[0471]

[0472] Example U-2 was prepared in a similar manner to that describedfor U-1, except that 3-methyl-4-isopropylaniline was used in place of6-amino-2-methylquinoline in step (a): mp 143-144° C.; HPLC R_(t)=15.7min.; TLC R_(f)=0.4 (2% methanol/dichloromethane); ¹H NMR (300 MHz,DMSO-d₆) δ 10.04 (s, 1H), 8.45 (s, 1H), 8.40 (d, 1H, J=4.5 Hz),7.82-7.76 (m, 2H), 7.67 (d, 1H, J=7.5 Hz), 7.55-7.41 (m, 4H), 7.32-7.28(m, 1H), 7.20 (d, 1H, J=8.3 Hz), 3.12-3.03 (m, 1H), 2.98 (s, 4H), 2.29(s, 3H), 1.18 (d, 6H, J=6.8 Hz); HRMS (FAB) calcd for C₂₄H₂₆N₂O [M+H]+359.2123, found 359.2117.

EXAMPLE V-1N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-ylsulfanylmethyl]phenyl}-(3-bromo-4-methyl)Benzamide

[0473]

[0474] (a) To a solution of 3-amino benzyl alcohol (123 mg, 1 mmol),3-bromo-4-methylbenzoic acid (215 mg, 1 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 380 mg, 1 mmol) in 5 mL DMF was added 0.14 mLof triethylamine (1 mmol) and the reaction mixture stirred at 50° C. for1 h. The solvent was removed in vacuo and the residue was purified bychromatography to obtain3-bromo-N-[3-hydroxymethyl)phenyl]-4-methylbenzamide, V-1a, (310 mg,96%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.03 (s, 1H), 7.97 (s, 1H), 7.67 (d,1H, J=7.5 Hz), 7.52 (s, 1H), 7.43 (d, 1H, J=7.6 Hz), 7.28 (d, 1H, J=6.9Hz), 7.06 (m, 1H), 6.81-6.84 (d, 1H, J=7.1 Hz), 5.01 (br s, 1H), 4.27(d, 2H, J=4.5 Hz), 2.20 (s, 3H); APCIMS m/z 338 [M+H]⁺.

[0475] (b) To 3-bromo-N-[3-hydroxymethyl)phenyl]-4-methylbenzamide,V-1a, (310 mg, 0.96 mmol) was added 5 mL of thionyl chloride and thereaction mixture stirred for 15 min. Thionyl chloride was removed invacuo and the crude dissolved in ethyl acetate and filtered through aplug of silica gel. The filtrate and washings were combined and thesolvent removed to obtain3-bromo-N-[3-chloromethyl)phenyl]-4-methylbenzamide, V-1b (217 mg, 66%):¹H NMR (300 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.30 (s, 1H), 7.97-8.01 (m,2H), 7.83 (d, 1H, J=8.3 Hz), 7.62 (d, 1H, J=8.3 Hz), 7.42-7.49 (m, 1H),7.27 (d, 1H, J=7.5 Hz), 4.87 (s, 2H), 2.52 (s, 3H).

[0476] (c) To a solution of 97 mg (0.64 mmol) of4-mercapto-1H-pyrazolo-[3,4-d]pyrimidine in 2 mL of DMF was added NaHCO₃(80 mg) and 217 mg (0.64 mmol) of3-bromo-N-[3-chloromethyl)phenyl]-4-methylbenzamide, V-1b. The reactionmixture stirred at 50° C. for 2 h. The solvent was removed and water wasadded to the residue. The resulting solid was filtered, washed withwater and dried. The desiredN-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-ylsulfanylmethyl]phenyl}-(3-bromo-4-methy)benzamide,V-1, was obtained by silica gel column chromatography purification (85mg, 30%): ¹H NMR (300 MHz, DMSO-d₆) δ 14.14 (s, 1H), 10.31 (s, 1H), 8.82(s, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 7.9-7.93 (m, 2H), 7.71 (d, 1H,J=6.8 Hz), 7.54 (d, 1H, J=7.9 Hz), 7.34 (dd, 1H, J=7.50, 7.9 Hz), 7.25(d, 1H, J=6.8 Hz), 4.73 (s, 2H), 2.54 (s, 3H): APCIMS m/z 454 [M+H]⁺.

EXAMPLE V-2N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-ylsulfanylmethyl]phenyl}-3,5-bis(Trifluoromethyl)Benzamide

[0477]

[0478] Example V-2 was prepared in a similar manner to that describedfor V-1, except that 3,5-bis(trifluoromethyl)benzoic acid was used inplace of 3-bromo-4-methylbenzoic acid in step (a): ¹H NMR (300 MHz,DMSO-d₆) δ 14.05 (s, 1H), 10.60 (s, 1H), 8.73 (s, 1H), 8.52 (s, 2H),8.31 (s, 1H), 8.23 (s, 1H), 7.82 (s, 1H), 7.63 (d, 1H, J=7.5 Hz),7.20-7.32 (m, 2H), 4.66 (s, 2H); APCIMS m/z 498 [M+H]⁺.

EXAMPLE V-3N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-hydroxy-3-methoxy)Benzamide

[0479]

[0480] Example V-3 was prepared in a similar manner to that describedfor V-1, except that 4-hydroxy-3-methoxybenzoic acid was used in placeof 3-bromo-4-methylbenzoic acid in step (a):¹H NMR (300 MHz, DMSO-d₆) δ14.05 (s, 1H), 9.93 (s, 1H), 9.63 (s, 1H), 8.72 (s, 1H), 8.23 (s, 1H),7.81 (s, 1H), 7.58 (m, 1H), 7.43 (s, 2H), 7.13-7.25 (m, 2H), 6.78-6.80(m, 1H), 4.66 (s, 2H), 3.27 (s, 3H); APCIMS rt/z 408 [M+H]⁺.

EXAMPLE V-4N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-hydroxy-3-t-butyl)Benzamide

[0481]

[0482] Example V-4 was prepared in a similar manner to that describedfor V-1, except that 3-t-butyl-4-hydroxybenzoic acid was used in placeof 3-bromo-4-methylbenzoic acid in step (a): ¹H NMR (300 MHz, DMSO-d₆) δ13.96 (s, 1H), 9.91 (s, 1H), 9.83 (s, 1H), 8.63 (s, 1H), 8.14 (s, 1H),7.71 (s, 1H), 7.57 (s, 1H), 7.47-7.53 (m, 2H), 7.11 (dd, 1H, J=7.9, 8.0Hz), 7.01 (d, 1H, J=7.2 Hz), 6.69 (d, 1H, J=8.3 Hz), 4.52 (s, 2H), 1.22(s, 9H); APCIMS m/z 434 [M+H]⁺.

EXAMPLE V-5N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-4-t-butylbenzamide

[0483]

[0484] Example V-5 was prepared in a similar manner to that describedfor V-1, except that 4-t-butylbenzoic acid was used in place of3-bromo-4-methylbenzoic acid in step (a): ¹H NMR (300 MHz, DMSO-d₆) δ14.05 (s, 1H), 10.02 (s, 1H), 8.73 (s, 1H), 8.23 (s, 1H), 7.85 (s, 1H),7.79 (d, 2H, J=8.3 Hz), 7.61 (d, 1H, J=7.6 Hz), 7.46 (d, 2H, J=8.3 Hz),7.23 (dd, 1H, J=7.50, 7.9 Hz), 7.13 (d, 1H, J=7.6 Hz), 4.68 (s, 2H),1.25 (s, 9H); APCIMS m/z 418 [M+H]⁺.

EXAMPLE V-6N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-phenoxy)Benzamide

[0485]

[0486] (a) To 3-aminobenzyl alcohol (1.23 g, 10 mmol) was added 20 mL ofthionyl chloride and the reaction was stirred at room temperature when ayellow solid separated out within five min. The reaction was monitoredby TLC for completion and excess thionyl chloride was removed in vacuoto obtain the hydrochloride salt of 3-aminobenzylchloride (V-6a). To4-mercapto-1H-pyrazolo-[3,4-d]pyrimidine (1.5 g, 10 mmol) in 5 mL of DMFwas added 4.6 mL of diisopropylethylamine (25 mmol) followed by theaddition of the hydrochloride salt of 3-aminobenzylchloride (V-6a) andthe reaction mixture stirred at 50° C. for 1 h. The solvent was removedin vacuo and the product3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]aniline, V-6b,crystallized (1.1 g, 42%): ¹H NMR (300 MHz, DMSO-d₆) δ 14.13 (s, 1H),8.79 (s, 1H), 8.31 (s, 1H), 7.18 (dd, 1H, J=8.0, 8.3 Hz), 6.80 (d, 1H,J=8.3 Hz), 4.64 (s, 2H); APCIMS m/z 258 [M+H]⁺.

[0487] (b) To a solution of 64.5 mg (0.25 mmol) of3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]aniline, V-6b, and53.5 mg (0.25 mmol) of 4-phenoxybenzoic acid in 2 mL DMF was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 95 mg, 0.25 mmol) and triethylamine (0.03 mL,0.25 mmol). The reaction was stirred at 50° C. for 1 h. After aconventional aqueous work-up,N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-phenoxy)benzamide,V-6, was obtained by chromatography on silica gel: ¹H NMR (300 MHz,DMSO-d₆) δ14.10 (s, 1H), 10.19 (s, 1H), 8.79 (s, 1), 8.30 (s, 1H), 7.97(d, 2H, J=8.7 Hz), 7.90 (s, 1H), 7.67 (d, 1H, J=8.3 Hz), 7.46 (dd, 2H,J=7.60, 8.3 Hz), 7.31 (d, H, J=7.6 Hz), 7.267 (d, 1H, J=8.3 Hz),7.19-7.22 (m, 2H), 7.07-7.12 (m, 3H), 4.70 (s, 2H); APCIMS m/z 454[M+H]⁺.

EXAMPLE V-6c

[0488] 0.1 M solutions of different acids, an amine template, HATU, andtriethylamine were prepared in anhydrous DMF. To each tube in an arrayof 8×11 culture tubes (10×75 mm) was added 105 μL (0.0105) of adifferent acid. To this was added 100 μL (0.01 mmol) of the aminesolution, 105 μL (0.0105 mmol) of the triethylamine solution followed by105 μL (0.0105 mmol) of theo-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumhexafluorophosphate solution. The reactions were stirred in a heatingblock at 50° C. for 3 h. The reaction mixtures were transferred to a 1mL 96-well-plates using a liquid handler. The solvents were removedusing the SpeedVac™ apparatus and the crude reaction mixtures wereredissolved in DMSO to give a final theoretical concentration of 10 mM.

EXAMPLE V-6d

[0489] Using the general procedure described in Example V-6c above, thefollowing compounds were made:

EXAMPLE V-7N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl]phenyl}-N′-[3,5-bis-(trifluoromethyl)Phenyl]Urea

[0490]

[0491] To a solution of 64.5 mg (0.25 mmol) of3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanyl-methyl]aniline, V-6b, and3,5-bis(trifluromethyl)phenyl isocyanate (61.2 mg, 0.25 mmol) in 2 mLDMF was added 20 mg of NaHCO₃ and the reaction stirred at 50° C. for 1h. After conventional aqueous work-up, purification by silica gelchromatography providedN-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl]phenyl}-N-[3,5-bis-(trifluoromethyl)phenyl]urea,V-7: ¹H NMR (300 MHz, DMSO-d₆) δ 14.09 (s, 1H), 9.34 (s, 1H), 9.01 (s,1H), 8.78 (s, 1H), 8.29 (s, 1H), 8.12 (s, 2H), 7.63 (s, 2H), 7.37 (d,1H, J=7.5 Hz), 7.25 (dd, 1H, J=7.6, 8.3 Hz), 7.12 (d, 1H, J=7.6 Hz),4.68 (s, 2H); APCIMS m/z 513 [M+H]⁺.

EXAMPLE V-7a

[0492] 0.1 M solutions of the amine template, HATU, and isocyanate wereprepared in anhydrous DMF. To each tube in an array of 8×11 culturetubes (10×75 mm) was added 100 μL (0.01 mmol) of the amine solution. Tothis was added 100 μL (0.01 mmol) of a different isocyanate solutionfollowed by the addition of 10 mg of sodium bicarbonate. The reactionswere stirred at 50° C. for 2 h. The reaction mixtures were transferredto a 1 mL 96-well plate using a liquid handler. The solvents wereremoved using the SpeedVac™ apparatus and the crude reaction mixtureswere redissolved in DMSO to give a final theoretical concentration of 10mM.

EXAMPLE V-7b

[0493] Using the general procedure described in Example V-7a above, thefollowing compounds were made:

EXAMPLE V-8N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl]phenyl}-N′-(pyridin-3-yl)Urea

[0494]

[0495] Example V-8 was prepared in a manner similar to that described inExample V-7, except that 3,5-bis(trifluromethyl)phenyl isocyanate wasreplaced by 3-pyridyl isocyanate: HPLC R_(t)=7.12 min.; ¹H NMR (300 MHz,DMSO-d₆) δ 14.12 (s, 1H), 8.79-8.84 (m, 3H), 8.59 (s, 1H), 8.30 (s, 1H),8.17 (s, 1H), 792 (d, 1H, J=8.3 Hz), 7.59 (s, 1H) 7.21-7.38 (m, 3H),7.09 (d, 1H, J=7.2 Hz), 4.67 (s, 2H); APCIMS m/z 377 [M+H]⁺.

EXAMPLE V-9N-{3-[(1H-pyrazolo[3,4d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(3,5-di-t-butyl)Benzamide

[0496]

[0497] Example V-9 was prepared in a manner similar to that described inExample V-6, except that 3,5-di-(t-butyl)benzoic acid was used in placeof 4-phenoxybenzoic acid in step (b): HPLC R_(t)=5.16 min.; ¹H NMR (300MHz, DMSO-d₆) δ 14.12 (s, 1H), 10.19 (s, 1H), 8.80 (s, 1H), 8.30 (s,1H), 7.87 (s, 1H), 7.72 (s, 2H), 7.66 (d, 2H, J=7.8 Hz), 7.60 (s, 1H),7.31 (dd, 1H, J=7.60, 7.9 Hz), 7.22 (d, 1H, J=7.5 Hz), 4.70 (s, 2H),1.33 (s, 18H); APCIMS m/z 474 [M+H]⁺.

EXAMPLE V-103-Bromo-4-hydroxy-N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-benzamide

[0498]

[0499] Example V-10 was prepared in a manner similar to that describedin Example V-6, except that 3-bromo-4-hydroxybenzoic acid was used inplace of 4-phenoxybenzoic acid in step (b): ¹H NMR (300 MHz, DMSO-d₆) δ10.07 (s, 1H), 8.79 (s, 1H), 8.30 (s, 1H), 8.14 (d, 1H, J=2.1 Hz), 7.88(s, 1H), 7.80 (dd, 1H, J=2.1, 8.1 Hz), 7.66 (d, 1H, J=8.6 Hz), 7.29 (dd,1H. J=7.7, 7.8 Hz), 7.18 (d, 1H, J=7.6 Hz), 7.01 (d, 1H, J=8.5 Hz), 4.69(s, 2H); APCIMS m/z 456 [M+H]⁺.

EXAMPLE V-11N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl)-quinoline-6-carboxamide

[0500]

[0501] Example V-11 was prepared in a manner similar to that describedin Example V-6, except that quinoline-6-carboxylic acid was used inplace of 4-phenoxybenzoic acid in step (b): ¹H NMR (300 MHz, DMSO-d₆) δ14.12 (s, 1H), 10.53 (s, 1H), 9.00 (dd, 1H, J=1.5, 4.2 Hz), 8.80 (s,1H), 8.61 (d, 1H, J=1.9 Hz), 8.52 (d, 1H, J=8.0 Hz), 8.30 (s, 1H), 8.23(dd, 1H, J=1.9, 8.7 Hz), 8.12 (d, 1H, J=8.7 Hz), 7.96 (s, 1H), 7.73 (d,1H, J=7.9 Hz), 7.64 (dd, 1H, J=4.5, 8.4 Hz), 7.34 (dd, 1H, J=7.9, 8.0Hz), 7.24 (d, 1H, J=7.5 Hz), 7.05-7.12 (m, 1H), 4.72 (s, 2H); APCIMS m/z413 [M+H]⁺.

EXAMPLE V-125-Fluoro-N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]-phenyl}-indole-2-carboxamide

[0502]

[0503] Example V-12 was prepared in a manner similar to that describedin Example V-6, except that 5-fluoroindole-2-carboxylic acid was used inplace of 4-phenoxybenzoic acid in step (b): ¹H NMR (300 MHz, DMSO-d₆) δ14.12 (s, 1H), 11.83 (s, 1H), 10.27 (s, 1H), 8.80 (s, 1H), 8.30 (s, 1H),7.91 (s, 1H), 7.73 (d, 1H, J=8.3 Hz), 7.47 (s, 1H), 7.44 (dd, 1H, J=4.1,4.60 Hz), 7.40 (d, 1H, J=1.9 Hz), 7.32 (dd, 1H, J=7.5, 8.0 Hz), 7.21 (d,1H, J=7.1 Hz), 7.05-7.12 (m, 1H), 4.71 (s, 2H); APCIMS m/z 419 [M+H]⁺.

EXAMPLE V-13N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-indole-6-carboxamide

[0504]

[0505] Example V-13 was prepared in a manner similar to that describedin Example V-6, except that indole-6-carboxylic acid was used in placeof 4-phenoxybenzoic acid in step (b): ¹H NMR (300 MHz, DMSO-d₆) δ 14.12(s, 1H), 11.45 (s, 1H), 10.18 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 8.04(s, 1H), 7.96 (s, 1H), 7.70 (d, 1H, J=7.9 Hz), 7.62 (s, 2H), 7.54 (s,1H), 7.31 (dd, 1H, J=7.9, 8.0 Hz), 7.18 (d, 1H, J=7.5 Hz), 7.30-6.52 (s,1H), 4.70 (s, 2H); APCIMS m/z 401 [M+H]⁺.

EXAMPLE V-14

[0506] The following compounds were made using the general proceduredescribed above in Example V-6c, except for the use of different acidsand amines, which yielded the products indicated below (wherein forconvenience, and as understood in the art, not all hydrogen atoms havebeen expressly indicated for each carbon and/or nitrogen atom).

EXAMPLE V-15(R/S)-2-(2-methylphenyl)-N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl)methyl}phenyl}butanamide

[0507]

[0508] Example V15 was prepared in a manner similar to that described inExample V-6, except that 3-(o-tolyl)-butyric acid was used in place of4-phenoxybenzoic acid in step (b): ¹H NMR (300 MHz, DMSO-d₆) δ 14.08 (s,1H), 9.95 (s, 1H), 8.76 (s, 1H), 8.26 (s, 1H), 7.71 (s, 1H), 7.50-7.48(d, 1H, J=8.31 Hz), 7.40-7.37 (dd, 1H, J=2.08, 8.31 Hz), 7.25-7.20 (d,1H, J=7.74, 7.93 Hz), 7.16-7.09 (m, 4H), 4.64 (s, 2H), 3.76-3.72 (dd,1H, J=5.48, 5.67 Hz), 2.38 (s, 3H), 1.99-1.92 (m, 1H), 1.63-1.60 (m,1H), 0.90-0.80 (t, 3H, J=7.18, 7.37 Hz); APCIMS m/z 418 [M+H]⁺.

EXAMPLE W-13-t-Butyl-4-hydroxy-N-{3-[5-(6-methoxy-pyridin-3-ylamino)-2H-pyrazol-3-ylmethylsulfanyl]-phenyl}-benzamide

[0509]

[0510] (a) A solution of 3-t-butyl-4-hydroxy-benzoic acid (1.0 g, 5.2mmol, 1.0 eq) in acetic anhydride (5.0 mL) was treated with concentratedsulfuric acid (0.03 mL, 0.5 mmol, 0.1 eq). The clear reaction mixturewas warmed to 90° C. After 18 h, the resultant black solution wasconcentrated under reduced pressure and treated with 1.0 M hydrochloricacid (100 mL). The aqueous layer was extracted with ethyl acetate (3×50mL) and the combined organic extracts were washed with water (50 mL),brine (50 mL), dried over magnesium sulfate, filtered, and concentratedunder reduced pressure to give a brown solid (1.2 g). The crude productwas purified by radial chromatography over silica gel using 10-20% ethylacetate/cyclohexane with 0.1% acetic acid to give4-acetoxy-3-t-butyl-benzoic acid, W-1a, as a white solid (309 mg, 26%):mp 123-125° C.; TLC Rf=0.6 (20% ethyl acetate/cyclohexane with 0.1%acetic acid); IR (KBr) 3418 (br), 1789, 1766 cm-1; 1H NMR (300 MHz,DMSO-d₆) δ 8.12 (d, 1H, J=2.1 Hz), 8.06 (dd, 1H, J=8.4, 2.1 Hz), 7.36(d, 1H, J=8.4 Hz), 2.39 (s, 3H), 1.36 (S, 9H).

[0511] (b). A slurry of 3-mercaptoaniline (1.00 mL, 9.42 mmol),2-chloro-N-methoxy-N-methyl-acetamide and cesium carbonate (6.12 g,18.84 mmol) in 5 mL of acetone was stirred for 18 h. The reactionmixture was partitioned between ethyl acetate (30 mL) and sat. sodiumcarbonate (2×50 mL) and the organic layer concentrated to dryness togive an amber oil. Purification by chromatography on silica gel usinghexane/ethyl acetate (1:1) afforded 1.57 g (56%) of2-(3-aminophenylsulfanyl)-N-methoxy-N-methyl-acetamide, W-1b, as a clearoil. HPLC R_(t)=5.85 min; ¹H NMR (300 MHz, CDCl₃) δ 7.26 (s, 1H), 7.08(t, 1H, J=8.1 Hz), 6.84-6.82 (m, 2H), 6.54 (d, 1H, J=8.7 Hz), 3.82 (s,2H), 3.75 (s, 3H), 3.22 (s, 3H).

[0512] (c) To a solution of 0.24 g (0.81 mmol) of2-(3-amino-phenylsulfanyl)-N-methoxy-N-methyl-acetamide, W-1b, indichloromethane (3 mL) was added 0.18 g (0.89 mmol) of3-t-butyl-4-acetoxy-benzoic acid, W-1b, and EDC (0.18 g, 0.97 mmol).After 18 h, the reaction was partitioned between ethyl acetate (30 mL)and sat. sodium bicarbonate (2×20 mL) and washed with 1N HCl (2×20 mL).The organic layer was dried over sodium sulfate and concentrated to agive yellow oil, which was purified by chromatography on silica gelusing hexane/ethyl acetate (1:1) as eluant to afford4-acetoxy-3-t-butyl-N-{3-[(methoxy-methyl-carbamoyl)-methylsulfanyl]-phenyl}benzamide,W-1c, as a colorless oil, 0.31 g (86%). HPLC R_(t)=13.65 min.; ¹H NMR(300 MHz, CDCl₃) δ 8.41 (br s, 1H), 7.94 (d, 1H, J=2.1 Hz), 7.75 (t, 1H,J=1.8 Hz), 7.63 (dd, 1H, J=8.4, 2.1 Hz), 7.57-7.53 (m, 1H), 7.28-7.15(m, 2H), 7.03 (d, 1H, J=8.4 Hz), 5.30 (s, 1H), 3.83 (s, 2H), 3.72 (s,3H), 3.18 (s, 3H), 2.36 (s, 3 h), 1.36 (s, 9H).

[0513] LCESI: Calculated for C₂₃H₂₈N₂O₅S (M+H⁺): 445, Found: 445.

[0514] (d). To a solution of 0.30 g (0.68 mmol) of4-acetoxy-3-t-Butyl-N-{3-[(methoxy-methyl-carbamoyl)-methylsulfanyl]-phenyl}benzamide,W-1c, in 7 mL of methanol/acetone/water (1:5:1) was added was potassiumcarbonate (0.55 g, 1.35 mmol). The reaction mixture was stirred for 1 hat room temperature and then partitioned between 1N HCl (2×20 mL) andethyl acetate (30 mL). The organic dried over sodium sulfate andconcentrated to give a yellow oil. Trituration with diethyl ether (2×5mL) gave 0.22 g (81%) of3-t-butyl-4-hydroxy-N-{3-[(methoxy-methyl-carbamoyl)-methylsulfanyl]-phenyl}benzamide,W-1d, as a white solid: HPLC Rt=13.12 min.; ¹H NMR (300 MHz, CDCl₃) δ8.04 (d, 1H, J=2.1 Hz), 8.00 (br s, 1H), 7.85 (dd, 1H, J=8.4, 2.4 Hz),7.74 (d, 1H, 7.8 Hz), 7.49 (t, 1H, J=7.8 Hz), 7.39 (d, 1H, J=7.5 Hz),7.02 (d, 1H, J=8.4 Hz), 4.13 (s, 2H), 3.95 (s, 3H), 3.41 (s, 3H), 1.64(s, 9H). LCESI: Calculated for C₂₁H₂₆N₂O₄S (M+H⁺): 403, Found: 403.

[0515] (e). To a solution of 0.24 g (1.31 mmol) ofN-(6-methoxy-pyridin-3-yl)-thioacetamide in anhydrous THF (5 mL) at −78°C. was added dropwise 1.32 mL (2.64 mmol) of LDA (2.0 M in THF). Thereaction mixture was stirred for 0.25 h at −78° C., warmed to 0° C. for1 h, and then recooled to −78° C. To the resulting solution was addeddropwise over a 5 min period a solution of 0.17 g (0.41 mmol) of3-t-butyl-4-hydroxy-N-{3-[(methoxy-methyl-carbamoyl)-methylsulfanyl]-phenyl}benzamide,W-1d, in 5 mL of THF. After 1 h at 0° C., the reaction was quenched withmethanol/acetic acid (0.5 mL:0.5 mL) and then partitioned between 30 mLof ethyl acetate and sat. sodium carbonate (2×20 mL). The organic layerwas concentrated to give a yellow oil, which was purified bychromatography on silica gel (1:1 hexane/ethyl acetate) to afford 0.22 g(96%) of3-t-Butyl-4-hydroxy-N-{3-[3-(6-methoxy-pyridin-3-ylthiocarbamoyl)-2-oxo-propylsulfanyl]-phenyl}benzamide,W-1e, as a pale yellow foam: HPLC Rt=13.12 min.; ¹H NMR (300 MHz, CDCl₃)δ 8.23-8.18 (m, 1H), 8.08-7.98 (m, 2H), 7.86-7.70 (m, 2H), 7.58-7.40 (m,2H), 7.28-7.15 (m, 2H), 6.82-6.68 (m, 2H). 3.94 (s, 3H), 3.89 (s, 2H),2.74 (s, 2H). 1.36 (s, 9H). LCESI: Calculated for C₂₇H₂₉N₃O₄S₂ (M+H⁺):524, Found: 524.

[0516] (f) To a solution of 0.18 g (0.33 mm ol) of3-t-butyl-4-hydroxy-N-{3-[3-(6-methoxy-pyridin-3-ylthiocarbamoyl)-2-oxo-propylsulfanyl]-phenyl}-benzamide,W-1e, in ethanol (2 mL) was added hydrazine mono-hydrate (0.25 mL, 0.50mmol) and acetic acid 0.025 mL, 0.28 mL). After 2 h, the reactionsolution was concentrated and the residue was purified by chromatography(4:1 hexane:ethyl acetate) to afford 0.11 g (62%) of3-t-Butyl-4-hydroxy-N-{3-[5-(6-methoxy-pyridin-3-ylamino)-2H-pyrazol-3-ylmethylsulfanyl]-phenyl}-benzamide,W-1: HPLC Rt=13.65 min.; ¹H NMR (300 MHz, CDCl₃) δ 7.88 (br s, 1H), 7.73(d, 1H, J=2.4 Hz), 7.71 (s, 1H), 7.53 (dd, 1H, J=8.4, 2.4 Hz), 7.44 (brs, 1H), 7.17 (t, 1H, J=7.8 Hz), 7.02 (d, 1H, J=7.8 Hz), 7.71 (d, 1H,J=8.4 Hz), 7.55 (d, 1H J=8.7 Hz), 5.64 (s, 1H), 5.39 (s, 1H), 4.03 (s,2H), 3.71 (s, 3H), 1.33 (s, 9H); LCESI: Calculated for C₂₇H₂₉N₅O₃S(M+H⁺): 504, Found: 504. Anal. calc'd for C₂₇H₂₉N₅O₃S0.3 CH₂Cl₂: C,61.97; H, 5.64; N, 13.24. Found C, 61.78; H, 5.67; N, 13.16.

EXAMPLE W-23-t-Butyl-4-hydroxy-N-[3-(pyridin-3-ylmethylsulfanyl)-phenyl]-benzamide

[0517]

[0518] Example W-2 was prepared in a similar manner to that describedfor the preparation of the intermediate3-t-butyl-4-hydroxy-N-{3-[(methoxy-methyl-carbamoyl)-methylsulfanyl]-phenyl}benzamide,W-1d, in example W-1, except that 3-picolyl chloride hydrochloride wasused in place of 2-chloro-N-methoxy-N-methyl-acetamide in step (b): mp95-100° C.; HPLC R_(t)=14.0 min.; TLC R_(f)=0.5 (5%methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ 10.15 (s, 1H),10.04 (s, 1H), 8.60 (s, 1H), 8.48 (d, 1H, J=3.6 Hz), 7.88 (s, 1H),7.84-7.72 (m, 3H), 7.64 (d, 1H, J=8.1 Hz), 7.40-7.29 (m, 2H), 7.10 (d,1H, J=8.0 Hz), 6.92 (d, 1H, J=8.4 Hz), 4.32 (s, 2H), 1.46 (s, 9H); MS(ESI) m/z 393 [M+H]⁺. Anal. calc'd for C₂₃H₂₄N₂O₂S.0.5 MTBE: C, 72.63;H, 7.16; N, 6.22; S, 7.12. Found: C, 70.40; H, 6.86; N, 6.44; S, 7.17.

EXAMPLE W-33-t-Butyl-4-hydroxy-N-[3-(isoquinolin-4-ylmethylsulfnyl)-phenyl]-benzamide

[0519]

[0520] Example W-3, isolated as the hydrochloride salt as described inExample K-2, was prepared in a similar manner to that described for thepreparation of the intermediate3-t-butyl-4-hydroxy-N-{3-[(methoxy-methyl-carbamoyl)-methylsulfanyl]-phenyl}benzamide,W-1d, in example W-1, except that 4-chloromethylisoquinolinehydrochloride, K-1c, was used in place of2-chloro-N-methoxy-N-methyl-acetamide in step (b): mp 205-210° C.; HPLCR_(t)=15.2 min.; TLC R_(f)=0.4 (5% methanol/dichloromethane); ¹H NMR(300 MHz, DMSO-d₆) δ 10.28 (s, 1H), 10.15 (s, 1H), 9.81 (s, 1H),8.66-8.59 (m, 3H), 8.32 (t, 1H, J=7.8 Hz), 8.11 (t, 1H, J=7.6 Hz), 7.95(s, 1H), 7.88 (d, 1H, J=2.0 Hz), 7.83 (dd, 1H, J=8.0, 2.0 Hz), 7.75 (d,1H, J=9.0 Hz), 7.41 (t, 1H, J=8.0 Hz), 7.22 (d, 1H, J=7.7 Hz), 7.02 (d,1H, J=8.4 Hz), 4.95 (s, 2H), 1.52 (s, 9H); MS (ESI) m/z 443 [M+H]⁺.Anal. calc'd for C₂₇H₂₆N₂O₂S.HCl 0.2H₂O: C, 66.45; H, 5.78; N, 5.743; S,6.54. Found: C, 66.20; H, 6.23; N, 5.37; S, 6.13.

EXAMPLE X-1N-[3-(5-Bromo-pyridin-3-ylmethoxy)-phenyl]-3-1-butyl-4-hydroxy-benzamide

[0521]

[0522] (a) To a solution of 156 mg (1.43 mmol) of 3-aminophenol in DMFat 0° C. was added 115 mg (2.86 mmol) of 60% sodium hydride dispersionin mineral oil. After 45 min, a slurry of 380 mg (1.57 mmol) of5-bromo-3-chloromethylpyridine hydrochloride, X-1a, which was preparedfrom 5-bromo-3-(hydroxymethyl)pyridine (Hamel, P. et al., J. Med. Chem.,40, 2866-2875 (1997)) according to the procedure described in ExampleK-1, step (c), in DMF was added. The reaction was allowed to slowly warmto room temperature over 3 h and then partitioned between MTBE and sat.aq. ammonium chloride. The organic layer was washed with brine, driedover MgSO₄, and concentrated. The residue was purified by radialchromatography with a gradient of 0 to 1% methanol in 40% ethylacetate/cyclohexane to give 318 mg of3-(5-bromo-pyridin-3-ylmethoxy)aniline, X-1b, as a clear oil: ¹H NMR(300 MHz, DMSO-d₆) δ 8.68 (d, 1H, J=2.3 Hz), 8.64 (d, 1H, J=1.7 Hz),8.10 (t, 1H, J=2.0 Hz), 6.91 (t, 1H, J=8.0 Hz), 6.17-6.22 (m, 3H), 5.10(br s, 2H), 5.06 (s, 2H); MS (ESI) m/z 279/281 [M+H]⁺.

[0523] (b) To a solution of 280 mg (1.0 mmol)3-(5-bromo-pyridin-3-ylmethoxy)aniline, X-1b, in dichloromethane (10 mL)was sequentially added 326 mg (1.0 mmol) of3-t-butyl-4-(t-butyl-dimethylsilanyloxy)-benzoyl chloride, X-1c, (Trova,M. P. et al., J. Med. Chem., 36, 580-590 (1993)) and triethylamine (0.15mL, 1.1 mmol). The resultant clear solution was stirred for 18 h at roomtemperature and then the solvent was removed under reduced pressure. Thereaction mixture was treated with 5% sodium bicarbonate (100 mL) andextracted with 10% isopropanol/chloroform (3×50 mL). The combinedorganic extracts were washed with brine (50 mL), dried over magnesiumsulfate, filtered, and concentrated under reduced pressure to give anoff-white solid (569 mg). The crude product was purified by radialchromatography over silica gel using 1-2% methanol/dichloromethane togiveN-[3-(5-bromo-pyridin-3-ylmethoxy)-phenyl]-3-t-butyl-4-(t-butyl-dimethyl-silanyloxy)-benzamide,X-1d, as a white solid (456 mg, 80%): HPLC R_(t)=20.6 min; TLC R_(f)=0.8(4% methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ 9.91 (s, 1H),8.53-8.51 (m, 2H), 8.00 (t, 1H, J=2.0 Hz), 7.64 (d, 1H, J=2.3 Hz), 7.56(dd, 1H, J=8.5, 2.2 Hz), 7.41 (t, 1H, J=2.0 Hz), 7.19-7.16 (m, 1H), 7.09(t, 1H, J=8.1 Hz), 6.78 (d, 1H, J=8.4 Hz), 6.60 (dd, 1H, J=8.0, 1.6 Hz),5.00 (s, 2H), 1.23 (s, 9H), 0.86 (s, 9H), 0.20 (s, 6H); MS (ESI) m/z569/571 [M+H]⁺.

[0524] (c) To a solution of 100 mg (0.18 mmol)N-[3-(5-bromo-pyridin-3-ylmethoxy)-phenyl]-3-t-butyl-4-(t-butyl-dimethyl-silanyloxy)-benzamide,X-1d, in THF (7 mL) at 0° C. was added a 1.0 M solution oftetrabutylammonium fluoride in THF (0.27 mL, 0.27 mmol). The slightlyyellow reaction mixture was warmed to room temperature over severalhours and stirred an additional 15 h. The cloudy reaction mixture wasconcentrated under reduced pressure to give a clear oil. The crudeproduct was purified by radial chromatography over silica gel using 2-4%methanol/dichloromethane to giveN-[3-(5-bromo-pyridin-3-ylmethoxy)-phenyl]-3-t-butyl-4-hydroxy-benzamide,X-1, as a white solid (75 mg, 91%): mp 105-111° C.; HPLC R_(t)=14.7min.; TLC R_(f)=0.4 (4% methanol/dichloromethane); ¹H NMR (300 MHz,DMSO-d₆) δ 10.11 (s, 1H), 10.01 (s, 1H), 8.74-8.72 (m, 2H), 8.21 (t, 1H,J=2.0 Hz), 7.78 (d, 1H, J=2.1 Hz), 7.72 (dd, 1H, J=8.3, 2.2 Hz), 7.61(t, 1H, J=2.0 Hz), 7.40-7.37 (m, 1H), 7.29 (t, 1H, J=8.1 Hz), 6.91 (d,1H, J=8.4 Hz), 6.79 (dd, 1H, J=7.8, 2.1 Hz), 5.20 (s, 2H), 1.43 (s, 9H);¹³C NMR (75 MHz, DMSO-d₆) δ 166.1, 159.5, 158.4, 150.1, 147.9, 141.2,138.3, 135.4, 135.3, 129.7, 127.2, 127.1, 125.4, 120.5, 115.9, 113.5,109.9, 107.2, 66.3, 34.8, 29.5; MS (ESI) m/z 455/457 [M+H]⁺. Anal.calc'd for C₂₃H₂₃BrN₂O₃: C, 60.67; H, 5.09; Br, 17.55; N, 6.15. Found:C, 60.63; H, 5.24; Br, 17.69; N, 6.01.

EXAMPLE X-24-Acetoxy-3-t-butyl-N-[3-(pyridin-3-ylmethoxy)phenyl]-benzamide

[0525]

[0526] Example X-2 was prepared from 3-(pyridin-3-ylmethoxy)aniline,X-2a, prepared from 3-picolylchloride hydrochloride and 3-hydroxyanilineas described in Example X-1, step (a), and 4-acetoxy-3-t-butylbenzoicacid, W-1a, according to the procedure described in Example W-1, step(c): mp 58-62° C.; HPLC R_(t)=14.4 min.; TLC R_(f)=0.3 (4%.methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (s, 1H),8.70 (s, 1H), 8.56 (d, 1H, J=4.3 Hz), 7.91-7.80 (m, 3H), 7.58-7.56 (m,1H), 7.46-7.21 (m, 4H), 6.81-6.78 (m, 1H), 5.16 (s, 2H), 2.37 (s, 3H),1.36 (s, 9H); MS (ESI) m/z 419 [M+H]⁺. Anal. calc'd forC₂₅H₂₆N₂O₄.0.4H₂O: C, 70.53; H, 6.35; N, 6.58. Found: C, 70.87; H, 6.28;N, 6.59.

EXAMPLE X-34-Acetoxy-3-t-butyl-N-[3-(isoquinolin-4-ylmethoxy)phenyl]-benzamide

[0527]

[0528] Example X-3 was prepared from 3-(isoquinolin-4-ylmethoxy)aniline,prepared from 4-chloromethylisoquinoline hydrochloride, K-1c, and3-hydroxyaniline as described in Example X-1, step (a), and4-acetoxy-3-t-butylbenzoic acid, W-1a, according to the proceduredescribed in Example W-1, step (c): mp 83-86° C.; HPLC R_(t)=15.6 min.;TLC R_(f)=0.3 (1% methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ10.26 (s, 1H), 9.37 (s, 1H), 8.67 (s, 1H), 8.21 (d, 1H, J=7.9 Hz), 8.14(d, 1H, J=8.8 Hz), 7.91-7.73 (m, 4H), 6.60 (t, 1H, J=2.2 Hz), 7.40-7.37(m, 1H), 7.30 (t, 1H, J=8.1 Hz), 7.22 (d, 1H, J=8.3 Hz), 6.90 (dd, 1H,J=7.6, 2.2 Hz), 5.56 (s, 2H), 2.36 (s, 3H), 1.36 (s, 9H); MS (ESI) m/z469 [M+H]⁺. Anal. calc'd for C₂₉H₂₈N₂O₄.0.2H₂O: C, 73.77; H, 6.06; N,5.93. Found: C, 73.46; H, 6.38; N, 5.82.

EXAMPLE X-43-t-Butyl-4-hydroxy-N-[3-(pyridin-3-ylmethoxy)-phenyl]-benzamide

[0529]

[0530] Example X-4 was prepared from4-acetoxy-3-t-butyl-N-[3-(pyridin-3-ylmethoxy)phenyl]-benzamide, X-2, ina manner similar to that described in Example W-1, step (d): mp 104-107°C.; HPLC R_(t)=13.6 min; TLC R_(f)=0.5 (5% methanol/dichloromethane); ¹HNMR (300 MHz, DMSO-d₆) δ 10.07 (s, 1H), 9.96 (s, 1H), 8.69 (s, 1H), 8.56(d, 1H, J=.4.0 Hz), 7.90 (d, 1H, J=7.9 Hz), 7.74-7.67 (m, 2H), 7.57 (s,1H), 7.47-7.42 (m, 1H), 7.35-7.33 (m, 1H), 7.24 (t, 1H, J=8.0 Hz), 6.87(d, 1H, J=8.3 Hz), 6.77-6.74 (m, 1H), 5.15 (s, 2H), 1.40 (s, 9H); ¹³CNMR (75 MHz, DMSO-d₆) δ 166.1, 159.5, 158.6, 149.5, 149.4, 141.2, 136.0,135.4, 133.0, 130.0, 127.2, 127.1, 125.4, 124.0, 115.9, 113.3, 109.9,107.2, 67.2, 34.5, 29.5; MS (ESI) m/z 375 [M−H]⁻.

[0531] Anal. calc'd for C₂₃H₂₄N₂O₃.0.5 MTBE: C, 72.83; H, 7.19; N, 6.66.Found: C, 72.61; H, 7.12; N, 6.66.

EXAMPLE X-53-t-Butyl-4-hydroxy-N-[3-(isoquinolin-4-ylmethoxy)-phenyl]-benzamide

[0532]

[0533] Example X-5 was prepared from4-acetoxy-3-t-butyl-N-[3-(isoquinolin-4-ylmethoxy)phenyl]-benzamide,X-3, in a manner similar to that described in Example W-1, step (d):HPLC R_(t)=14.8 min; TLC R_(f)=0.4 (4% methanol/dichloromethane); ¹H NMR(300 MHz, DMSO-d₆) δ 10.09 (s, 1H), 9.97 (s, 1H), 9.34 (s, 1H), 8.65 (s,1H), 8.20 (d, 1H, J=8.2 Hz), 8.13 (d, 1H, J=7.9 Hz), 7.90-8.86 (m, 1H),7.78-7.59 (m, 4H), 7.38-7.35 (m, 1H), 7.26 (t, 1H, J=8.0 Hz), 6.85 (d,2H, J=8.6 Hz), 5.54 (s, 2H), 1.38 (s, 9H); HRMS (FAB) calcd forC₂₇H₂₆N₂O₃ [M+H]+ 427.2022, found 427.2020.

EXAMPLE Y-1 1-[3-(pyridin-3-ylmethoxy)phenylcarbamoyl]pyrrolidine

[0534]

[0535] A solution of 100 mg (0.50 mmol) of3-(pyridin-3-ylmethoxy)aniline, X-2a, and 0.076 mL (0.55 mmol) oftriethylamine in 2 mL of dichloromethane was added dropwise to asolution of triphosgene (54 mg, 0.18 mmol) in 2 mL of dichloromethane.After 20 min, a solution of pyrrolidine (0.042 mL) and triethylamine(0.076 mL) in 2 mL of dichloromethane was added to the reaction mixture.After 2 h, the reaction was partitioned between dichloromethane and 5%aq. sodium bicarbonate. The organic layer was washed with water andbrine, dried over MgSO₄ and concentrated. The residue was purified byradial chromatography with a gradient of 0 to 2% methanol in 1:1 ethylacetate:cyclohexane to give 81 mg (55%) of1-[3-(pyridin-3-ylmethoxy)phenylcarbamoyl]pyrrolidine, Y-1, as a whitesolid: mp 138-140° C.; HPLC R_(t)=9.7 min.; TLC R_(f)=0.3 (5%methanol/dichloromethane); ¹H NMR (300 MHz, DMSO-d₆) δ 8.66 (d, 1H,J=1.7 Hz), 8.54 (dd, 1H, J=4.7, 1.5 Hz), 8.08 (s, 1H), 7.88-7.85 (m,1H), 7.45-7.41 (m, 1H), 7.35-7.34 (m, 1H), 7.16-7.09 (m, 2H), 6.61-6.58(m, 1H), 5.09 (s, 2H), 3.40-3.31 (m, 4H), 1.87-1.83 (m, 4H); ¹³C NMR (75MHz, DMSO-d₆) δ 158.5, 154.1, 149.4, 149.3, 142.3, 135.9, 133.1, 129.4,123.9, 112.4, 108.0, 106.3, 67.1, 46.0, 25.4; MS (ESI) m/z 298 [M+H]⁺.Anal. calc'd for C₁₇H₁₉N₃O₂: C, 68.67; H, 6.44; N, 14.13. Found: C,68.41; H, 6.50; N, 13.89.

EXAMPLE Y-2 4-[3-(pyridin-3-ylmethoxy)phenylcarbamoyl]morpholine

[0536]

[0537] Example Y-2 was prepared in a manner similar to that described inExample Y-1, except that morpholine was used in place of pyrrolidine: mp58-62° C.; HPLC R_(t)=8.7 min.; TLC R_(f)=0.3 (5% methanol/methylenechloride); ¹H NMR (300 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.84 (d, 1H, J=5.3Hz), 8.63 (s, 1H), 8.50 (d, 1H, J=7.8 Hz), 8.00-7.95 (m, 1H), 7.36 (s,1H), 7.16 (t, 1H, J=8.1 Hz), 7.07 (d, 1H, J=7.9 Hz), 6.65-6.63 (m, 1H),5.26 (s, 2H), 3.60 (t, 4H, J=4.5 Hz), 3.42 (t, 4H, J=4.5 Hz); ¹³C NMR(75 MHz, DMSO-d₆) δ 157.7, 155.0, 143.8, 141.9, 141.1, 136.9, 129.2,126.8, 112.6, 108.0, 106.2, 66.0, 65.4, 44.2; MS (ESI) m/z 314 [M+H]⁺.Anal. calc'd for C₁₇H₁₉N₃O₃ HCl-0.3H₂O: C, 57.48; H, 5.85; Cl, 9.98; N,11.83. Found: C, 57.05; H, 5.83; Cl, 9.99; N, 11.50.

EXAMPLE Z-13-[{6-Methoxy-7-(2-methoxyethoxy)Cinnolin-4-yl}sulfanylmethyl]-N-phenyl-benzamide

[0538]

[0539] (a) To a solution of 0.30 g (1.33 mmol) of3-(chloromethyl)-N-phenylbenzamide, Z-1a, which prepared in a mannersimilar to that described in Example A-1, step (a), in 6 mL of ethanolwas added 0.20 g (2.65 mmol) of thiourea, and the mixture was heated to80° C. After 3 h, 1.0 mL (3 mmol) of 2N aq. sodium hydroxide was added,and heating at 80° C. was continued. After an additional 2.5 h, thereaction was cooled to room temperature and 10 mL of water was added.The mixture was extracted with ethyl acetate, and the aqueous layer wasneutralized with 1N aq. HCl and extracted again with ethyl acetate. Thecombined organic layers were washed with water and with brine, driedover sodium sulfate, and concentrated. The residue was purified bychromatography on silica gel, eluting with a gradient of 15% to 30%ethyl acetate in hexane, to provide 174 mg of3-(mercaptomethyl)-N-phenylbenzamide, Z-1b: ¹H NMR (300 MHz, CDCl₃) δ7.85 (s, 2H), 7.75 (m, 1H), 7.67 (m, 2H), 7.53 (m, 1H), 7.40, (m, 3H),7.17 (m, 1H), 3.80 (d, 2H), 1.83 (t, 1H).

[0540] (b) To a solution of 50 mg (0.186 mmol) of4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline, Z-1c, (PCT applicationWO 97/34876, p.51) and 42.5 mg (0.189 mmol) of3-(mercaptomethyl)-N-phenylbenzamide, Z-1b, in 1.2 mL of isopropanol wasadded 12.3 mg of potassium hydroxide in 1.2 mL of ethanol. The mixturewas heated to 40° C. for 45 min, then cooled to room temperature. Theprecipitate was collected by filtration and air-dried to give 44.7 mg(47%) of3-[{6-methoxy-7-(2-methoxyethoxy)cinnolin-4-yl}sulfanylmethyl]-N-phenyl-benzamide,Z-1: ¹H NMR (300 MHz, DMSO-d₆) 810.29 (s, 1H), 9.19 (s, 1H), 8.10 (s,1H), 7.89 (m, 1H), 7.76 (m, 4H), 7.54 (m, 1H), 7.38 (m, 2H), 7.09 (m,2H), 4.72 (s, 2H), 4.38 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.32 (s,3H). MSESI⁽⁺⁾: M+H₊ 476, M+Na₊ 498, M+K₊ 514.

EXAMPLE AA-13-[2-(6-Acetylamino-pyridin-3-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethylphenyl)-benzamidedihydrochloride

[0541]

[0542] (a) To a solution of 5-bromo-pyridin-2-ylamine (Aldrich, 2.0 g,11.6 mmol, 1.0 eq) in tetrahydrofuran (100 mL) was added aceticanhydride (3.0 mL, 31.8 mmol, 2.7 eq) and triethylamine (1.8 mL, 12.8mmol, 1.1 eq). After 3 days, the solvent was removed and the crudereaction mixture was dissolved in ethyl acetate and sequentially washedwith aqueous 5% sodium bicarbonate and brine. The crude product wasdried over magnesium sulfate to give N-(5-bromo-pyridin-2-yl)-acetamide,AA-1a, as a white solid (2.5 g, 100%): HPLC R_(t) 8.4 min.; TLC R_(f)0.7 (2% methanol-dichloromethane); ¹H NMR (DMSO-d₆, 300 MHz) δ 10.62 (s,1H), 8.42 (dd, 1H, J=2.5, 0.7 Hz), 8.06 (d, 1H, J=9.0 Hz), 7.98 (dd, 1H,J=9.0, 2.4 Hz), 2.09 (s, 3H); ¹³C NMR (DMSO-d₆, 75 MHz) δ 169.8, 151.4,148.8, 140.8, 115.3, 113.5, 24.2; MS m/z 215/217 (M+H)⁺.

[0543] (b) To a solution of N-(5-bromo-pyridin-2-yl)-acetamide, AA-1a,(2.2 g, 10.2 mmol, 1.0 eq) in degassed N,N-dimethylformamide (100 mL)was added diisopropylethylamine (3.6 mL, 20.4 mmol, 2.0 eq), copper(I)iodide (155 mg, 0.82 mmol, 0.08 eq),dichlorobis(triphenylphosphine)palladium(II) (286 mg, 0.41 mmol, 0.04eq) and triethyl-ethynyl-silane (Aldrich, 3.7 mL, 20.4 mmol, 2.0 eq).The resultant red solution was warmed to 115° C. for 2 days. The crudereaction mixture was poured into water and extracted withmethyl-tert-butyl ether/ethyl acetate. The organic layer was washed withbrine, dried over magnesium sulfate and purified over silica, which waseluted with 10% ethyl acetate-cyclohexane, to giveN-(5-triethylsilanylethynyl-pyridin-2-yl)-acetamide, AA-1b, as a beigesolid (1.2 g, 44%): HPLC R_(t) 17.8 min.; TLC R_(f) 0.5 (20% ethylacetate-cyclohexane); ¹H NMR (DMSO-d₆, 300 MHz) δ 10.69 (s, 1H), 8.40(d, 1H, J=1.7 Hz), 8.08 (d, 1H, J=8.6 Hz), 7.84 (dd, 1H, J=8.7, 2.3 Hz),2.10 (s, 3H), 1.01 (t, 6H, J=7.8 Hz), 0.68 (q, 9H, J=7.8 Hz); MS (ESI)m/z 275 (M+H)⁺.

[0544] (c) To a solution ofN-(5-triethylsilanylethynyl-pyridin-2-yl)-acetamide, AA-1b, (1.0 g, 3.6mmol, 1.0 eq) in tetrahydrofuran (40 mL) was added a solution oftetrabutylammonium fluoride (4.0 mL, 1.0 M, 4.0 mmol, 1.1 eq). Theresultant amber solution was stirred at room temperature for 18 h. Thesolvent was removed under reduced pressure and the crude reactionmixture (1.1 g, tan solid) was dissolved in ethyl acetate and passedthrough a silica plug, which was eluted with ethyl acetate. Theresultant yellow solid (1.0 g) was washed with 10% MTBE-cyclohexane togive N-(5-ethynyl-pyridin-2-yl)-acetamide, AA-1c, as a tan solid (491mg, 84%): HPLC R_(t) 7.1 min.; TLC R_(f) 0.5 (30% ethylacetate-cyclohexane); ¹H NMR (DMSO-d₆, 300 MHz) δ 10.65 (s, 1H), 8.41(d, 1H, J=1.6 Hz), 8.08 (d, 1H, J=8.7 Hz), 7.86 (dd, 1H, J=8.6, 2.2 Hz),4.29 (s, 1H), 2.10 (s, 3H); ¹³C NMR (DMSO-d₆, 75 MHz) δ 169.5, 151.6,150.8, 141.0, 113.6, 112.7, 82.6, 80.5, 23.9; MS (ESI) m/z 161 (M+H)⁺.

[0545] (d) To a solution of 2-chloro-5-nitrobenzotrifluoride (Lancaster,16.5 mL, 112 mmol, 1.0 eq) and piperazine-1-carboxylic acid tert-butylester (Aldrich, 2.5 g, 134 mmol, 1.2 eq) in N,N-dimethylformamide (225mL) was added potassium carbonate (46.3 g, 336 mmol, 3.0 eq). Theresultant red solution was warmed to 90° C. for 24 h. The crude productwas poured into ice water (1.7 L) and extracted with ethyl acetate(3×300 mL). The combined organic extracts were diluted withmethyl-tert-butyl ether (1.0 L) and sequentially washed with water andbrine. The organic layer was dried over magnesium sulfate, filtered andconcentrated under reduced pressure to give4-(nitro-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butylester, AA-1d, as an orange solid (43.6 g, 104%): HPLC R_(t) 17.0 min.;TLC R_(f) 0.5 (20% ethyl acetate-cyclohexane); ¹H NMR (DMSO-d₆, 300 MHz)δ 8.46-8.40 (m, 2H), 7.62 (d, 1H, J=8.9 Hz), 3.48 (t, 4H, J=4.8 Hz),3.06 (t, 4H, J=5.0 Hz), 1.43 (s, 9H); MS (ESI) m/z 276 (M+H−BOC)⁺.

[0546] (e) To a solution of4-(nitro-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butylester, AA-1d, (43.6 g, 116 mmol) and 10% palladium on carbon (4.3 g) inethyl acetate (1.2 L) was added hydrogen (1 atm). The resultant slurrywas stirred for 18 h, filtered through celite and concentrated underreduced pressure to give4-[4-(t-butoxycarbonyl)piperazin-1yl]-3-trifluoromethylaniline, AA-1e,as a yellow solid (40 g, 92%): HPLC R_(t) 14.8 min.; TLC R_(f) 0.1 (10%ethyl acetate-cyclohexane); ¹H NMR (DMSO-d₆, 300 MHz) δ 7.22 (d, 1H,J=8.5 Hz), 6.82 (d, 1H, J=2.6 Hz), 6.75 (dd, 1H, J=8.5, 2.5 Hz), 5.37(s, 2H), 3.37 (br. s, 4H), 2.66 (t, 4H, J=4.8 Hz), 1.41 (s, 9H); MS(ESI) m/z 346 (M+H)⁺.

[0547] (f) To a solution of4-[4-(t-butoxycarbonyl)piperazin-1yl]-3-trifluoromethylaniline, AA-1e,(10.0 g, 29.0 mmol, 1.0 eq) and 3-iodobenzoic acid (Aldrich, 8.6 g, 34.8mmol, 1.2 eq) in ethyl acetate (300 mL) and dichloromethane (300 mL) wasadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.7g, 34.8 mmol, 1.2 eq). The resultant brown solution was stirred for 18h. The solvent was removed under reduced pressure and the crude productwas purified over silica, which was eluted with 10-20% ethylacetate-cyclohexane, to give4-({[1-(3-iodo-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, AA-1f, as a beige solid (10.3 g, 62%): HPLC R_(t)19.7 min.; TLC R_(f) 0.5 (30% ethyl acetate-cyclohexane); ¹H NMR(DMSO-d₆, 300 MHz) δ 10.53 (s, 1H), 8.32 (s, 1H), 8.14 (d, 1H, J=2.3Hz), 8.04 (dd, 1H, J=8.7, 2.3 Hz), 7.99-7.96 (m, 2H), 7.60 (d, 1H, J=8.8Hz), 7.36 (t, 1H, J=7.8 Hz), 3.44 (br. s, 4H), 2.51 (t, 4H, J=4.6 Hz),1.43 (s, 9H); MS (ESI) m/z 576 (M+H)⁺.

[0548] (g)4-[({1-[3-(6-Acetylamino-pyridin-3-ylethynyl)-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, AA-1g, was prepared in the manner similar to thatdescribed in example S-1, step (c) for ethyl3-isoquinolin-4-ylethynyl-benzoate, S-1c, except that4-({[1-(3-iodo-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, AA-1f, was used in place of 3-iodobenzoate andN-(5-ethynyl-pyridin-2-yl)-acetamide, AA-1c, was used in place of4-ethynyl-isoquinoline, S-1b: HPLC R_(t) 18.1 min.; TLC R_(f) 0.5 (2%methanol-dichloromethane); ¹H NMR (DMSO-d₆, 300 MHz) δ 10.71 (s, 1H),10.55 (s, 1H), 8.17 (s, 2H), 8.14 (s, 1H), 8.07 (dd, 1H, J=8.6, 2.4 Hz),8.01-7.96 (m, 2H), 7.80-7.78 (m, 1H), 7.65-7.58 (m, 2H), 3.44 (br. s,4H), 2.80 (t, 4H, J=4.8 Hz), 2.13 (s, 3H), 1.44 (s, 9H); MS (ESI) m/z608 (M+H)⁺.

[0549] (h) 4-{[(1-{3-[2-(6-Acetylamino-pyridin-3-yl)-ethyl]-phenyl1-methanoyl)-amino]-trifluoro-methyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1 h, was prepared in a manner similar to thatdescribed in example S-1, step (d) for3-(2-isoquinolin-4yl-ethyl)-benzoic acid ethyl ester, S-1d, except4-[({1-[3-(6-acetylamino-pyridin-3-ylethynyl)-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, AA-1 g, was used instead of ethyl3-(isoquinolin-4-ylethynyl)benzoate and the reduction was done at 45 psiof hydrogen in acetic acid-methanol-tetrahydrofuran: HPLC R, 17.1 min.;TLC R_(f) 0.6 (4% methanol-dichloromethane); ¹H NMR (DMSO-d₆, 300 MHz) δ10.40 (s, 1H), 10.35 (s, 1H), 8.16-8.14 (m, 2H), 8.05 (dd, 1H, J=8.8,2.4 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.84 (s, 1H), 7.81-7.77 (m, 1H), 7.64(dd, 1H, J=8.6, 2.4 Hz), 7.58 (d, 1H, J=8.8 Hz), 7.44 (d, 1H, J=4.8 Hz),3.44 (br. s, 4H), 2.98-2.91 (m, 4H), 2.80 (t, 4H, J=4.6 Hz), 2.06 (s,3H), 1.43 (s, 9H); MS (ESI) m/z 612 (M+H)⁺.

[0550] (i)3-[2-(6-Acetylamino-pyridin-3-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride, AA-1, was prepared in a manner similar to thatdescribed in example R-13, step (b) for4-fluoro-N-[4-(piperazin-1-yl)-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide,R-13, except 4-{[(1{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1h, was used in place of4-fluoro-N-[4-{t-butoxycarbonyl)piperazin-1-yl}-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide,R-13a, and the deprotection was done with HCl in ethanol instead oftrifluoroacetic acid in methylene chloride: HPLC R₁ 11.7 min.; TLC R_(f)0.4 (15% methanol-chloroform w/ 0.1% ammonium hydroxide); ¹H NMR(DMSO-d₆, 300 MHz) δ 10.97 (s, 1H), 10.52 (s, 1H), 9.23 (m, 2H),8.22-8.12 (m, 3H), 7.91-7.82 (m, 4H), 7.56 (d, 1H, J=8.8 Hz), 7.44 (d,2H, J=4.7 Hz), 3.17 (br. s, 4H), 3.07 (br. s, 4H), 2.97 (s, 4H), 2.12(s, 3H); MS (ESI) m/z 512 (M+H)⁺. Anal. calcd for C₂₇H₂₈F₃N₅O₂x2.0HClx1.2H₂O: C, 53.50; H, 5.39; N, 11.56; Cl, 11.70. Found: C, 53.44;H, 5.54; N, 11.19; Cl, 11.62.

EXAMPLE AA-23-[2-(6-Amino-pyridin-3-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamideDihydrochloride

[0551]

[0552] (a) To a solution of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1h, (100 mg, 0.16 mmol, 1.0 eq) in ethanol (3mL) was added aqueous sodium hydroxide (2.8 mL, 1.0 M, 2.8 mmol, 1.8eq). The clear solution was heated to 55° C. for 18 hours and pouredinto a mixture of aqueous 50% saturated sodium bicarbonate and ethylacetate. The organic layer was washed with brine, dried over magnesiumsulfate, filtered and purified by radial chromatography over silica,which was eluted with 3% methanol-chloroform with 0.1% ammoniumhydroxide, to give4-{[(1-{3-[2-(6-amino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-2a, as a white solid (54 mg, 59%): HPLC R_(t)17.0 min.; TLC R_(f) 0.5 (5% methanol-chloroform w/ 0.1% ammoniumhydroxide); ¹H NMR (DMSO-d₆, 300 MHz) δ 10.39 (s, 1H), 8.16 (d, 1H,J=2.4 Hz), 8.05 (dd, 1H, J=8.6, 2.2 Hz), 7.82-7.76 (m, 2H), 7.74 (dd,1H, J=2.0 Hz), 7.57 (d, 1H, J=8.8 Hz), 7.44-7.42 (m, 2H), 7.27 (dd, 1H,J=8.4, 2.4 Hz), 6.38 (d, 1H, J=8.4 Hz), 5.63 (s, 2H), 3.44 (br. s, 4H),2.92-2.72 (s, 8H), 1.43 (s, 9H); MS (ESI) m/z 570 (M+H)⁺.

[0553] (b)3-[2-(6-Amino-pyridin-3-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride, AA-2, was prepared in a manner similar to thatdescribed in example AA-1, step (i), except4-{[(1-{3-[2-(6-amino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-2a, was used in place of4-{[(1-{3[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1h: HPLC R_(t) 11.2 min.; ¹H NMR (DMSO-d₆, 300MHz) δ 13.89 (s, 1H), 10.59 (s, 1H), 9.33 (s, 2H), 8.23 (d, 1H, J=2.2Hz), 8.15-8.13 (m, 1H), 7.95-7.79 (m, 6H), 7.54 (d, 1H, J=8.7 Hz),7.45-7.43 (m, 2H), 6.96 (d, 1H, J=9.0 Hz), 3.17 (s, 4H), 3.08 (s, 4H),2.94-2.93 (m, 2H), 2.88-2.87 (m, 2H); MS (ESI) m/z 470 (M+H)⁺. Anal.calcd for C₂₅H₂₆F₃N₅Ox2.0 HCl: C, 55.36; H, 5.20; N, 12.91; Cl, 13.07.Found: C, 55.18; H, 5.16; N, 12.65; Cl, 13.28.

EXAMPLE BB-13-[2-(3H-Imidazo[4,5-b]pyridin-6-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamideDihydrochloride

[0554]

[0555] (a) To a solution of 5-bromo-3-nitro-pyridin-2-ylamine, BB-1a,(Lancaster, 8.9 g, 40.8 mmol, 1.0 eq) in ethanol (450 mL) was addedtin(II) chloride dihydrate (32.3 g, 143 mmol, 3.5 eq). The resultantyellow slurry was warmed to 60° C. for 4 h. The solvent was removedunder reduce pressure and the crude reaction mixture was treated with10% ammonium hydroxide and extracted with ethyl acetate. The combinedorganic extracts were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to give a black solid (7.5 g). Thecrude product was purified over silica (flash), which was eluted with2-7% methanol-ethyl acetate, to give 5-bromo-pyridine-2,3-diamine,BB-1b, as a grey solid (7.0 g, 91%): HPLC R_(t) 5.5 min.; TLC R_(f) 0.5(1% methanol-ethyl acetate); ¹H NMR (DMSO-d₆, 300 MHz) δ 7.28 (d, 1H,J=2.0 Hz), 6.80 (d, 1H, J=2.0 Hz), 5.60 (s, 2H), 4.99 (s, 2H); ¹³C NMR(DMSO-d₆, 75 MHz) δ 147.4, 134.0, 131.9, 119.1, 106.4; MS im/z 188/190(M+H)⁺.

[0556] (b) A round bottom flask was charged with5-bromo-pyridine-2,3-diamine, BB-1b, (4.6 g, 24.5 mmol) andtriethylformate (50 mL). The resultant purple slurry was warmed to 130°C. for 18 h. The solvent was removed under reduced pressure at 85° C.and the resultant brown oil was dissolved in ethanol (70 mL) and treatedwith concentrated HCl (30 mL). The resultant brown slurry was warmed to90° C. for 1 hour, concentrated under reduced pressure and treated withwater (100 mL). The pH was adjusted to 9 with concentrated ammoniumhydroxide and the aqueous layer was extracted with 10% isopropylalcohol-ethyl acetate (5×100 mL). The combined organic layers werewashed with aqueous 5% sodium bicarbonate, brine, dried over magnesiumsulfate and filtered to give 6-bromo-3H-imidazo[4,5-b]pyridine, BB-1c,as a brown solid (4.5 g, 94%): HPLC R_(t) 6.1 min.; ¹H NMR (DMSO-d₆, 300MHz) δ 13.35, 12.93 (2 br. s, 1H), 8.56 (s, 1H), 8.50 (d, 1H, J=1.6 Hz),8.37 (br. s, 1H); MS (ESI) m/z 196/198 (M−H)⁻. Anal. calcd for C₆H₄BrN₃:C, 36.39; H, 2.04; N, 21.22; Br, 40.35. Found: C, 36.21; H, 2.09; N,21.11; Br, 40.28.

[0557] (c) 6-Triethylsilanylethynyl-3H-imidazo[4,5-b]pyridine, BB-1d,was prepared in the manner similar to that described in example AA-1,step (b), except 6-bromo-3H-imidazo[4,5-b]pyridine, BB-1c, was used inplace of N-(5-bromo-pyridin-2-yl)-acetamide, AA-1a: HPLC R_(t) 14.8min.; TLC R_(f) 0.4 (5% methanol-methylene chloride); ¹H NMR (DMSO-d₆,300 MHz) δ 13.34, 12.88 (2 br. s, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 8.11(br. s, 1H), 1.03 (t, 9H, J=7.8 Hz), 0.70 (q, 6H, J=7.8 Hz); MS (ESI)m/z 258 (M+H)⁺.

[0558] (d) To a solution of6-triethylsilanylethynyl-3H-imidazo[4,5-b]pyridine, BB-1d, (1.4 g, 5.4mmol, 1.0 eq) in methanol (30 mL) was added aqueous sodium hydroxide(2.2 mL, 10 M, 22 mmol, 4.0 eq). The resultant brown solution was warmedto 40° C. for 24 h. The reaction mixture was poured into aqueous 5%sodium bicarbonate (200 mL) and the aqueous layer was extracted with 10%isopropyl alcohol-chloroform. The organic layer was washed with brine,dried over magnesium sulfate, filtered and concentrated under reducedpressure to give a yellow solid (1.3 g). The crude product was washedwith methyl-tert-butyl ether/cyclohexane (2:1) to give6-ethynyl-3H-imidazo[4,5-b]pyridine, BB-1e, as a yellow solid (750 mg,97%): HPLC R_(t) 5.1 min.; TLC R_(f) 0.5 (5% methanol-chloroform w/ 0.1%ammonium hydroxide); ¹H NMR (DMSO-d₆, 300 MHz) δ 13.16 (br. s, 1H), 8.52(s, 1H), 8.46 (d, 1H, J.=1.7 Hz), 8.14 (s, 1H), 4.26 (s, 1H); MS (ESI)m/z 144 (M+H)⁺.

[0559] (e)4-[({1-[3-(3H-Imidazo[4,5-b]pyridin-6-ylethynyl)-phenyl]-methanoyl}-amino)-trifluoro-methyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, BB-1f, was prepared in the manner similar to thatdescribed in example AA-1, step (g), except6-ethynyl-3H-[4,5-b]pyridine, BB-1e, was used instead ofN-(5-ethynyl-pyridin-2-yl)-acetamide, AA-1c: HPLC R_(t) 16.1 min.; TLCR_(f) 0.5 (5% methanol-chloroform w/ 0.1% ammonium hydroxide); ¹H NMR(DMSO-d₆, 300 MHz) δ 13.20 (br. s, 1H), 10.57 (s, 1H), 8.60 (d, 1H,J=1.5 Hz), 8.56 (s, 1H), 8.26-8.18 (m, 3H), 8.08 (dd, 1H, J=8.8, 2.2Hz), 7.83 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=8.0 Hz), 7.66-7.59 (m, 2H),3.44 (br. s, 4H), 2.81 (t, 4H, J=4.6 Hz), 1.44 (s, 9H); MS (ESI) m/z 591(M+H)⁺.

[0560] (f)4-{[(1-{3-[2-(3H-Imidazo[4,5-b]pyridin-6-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, BB-1g, was prepared in the manner similar to thatdescribed in example AA-1, step (h), except4-[({1-[3-(3H-[imidazo[4,5-b]pyridin-6-ylethynyl)-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, BB-1f, was used instead of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1 g: HPLC R, 15.4 min.; ¹H NMR (DMSO-d₆, 300MHz) δ 12.93, 12.56 (2br. s, 1H), 10.40 (s, 1H), 8.35 (s, 1H), 8.31 (br.s, 1H), 8.16 (d, 1H, J=2.4 Hz), 8.05 (dd, 1H, J=8.8, 2.2 Hz), 7.87 (s,1H), 7.80-7.78 (m, 2H), 7.58 (d, 1H, J=8.8 Hz), 7.46-7.41 (m, 2H), 3.44(br. s, 4H), 3.11-3.03 (m, 4H), 2.80 (t, 4H, J=4.6 Hz), 1.43 (s, 9H); MS(ESI) m/z 595 (M+H)⁺.

[0561] (g)3-[2-(3H-Imidazo[4,5-b]pyridin-6-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamide,BB-1, was prepared in the manner similar to that described in exampleAA-1, step (i), except4-{[(1-{3-[2-(3H-imidazo[4,5-b]pyridin-6-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, BB-1g, was used in place of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1h: HPLC R_(t) 10.0 min.; ¹H NMR (DMSO-d₆, 300MHz) δ 10.57 (s, 1H), 9.28 (br. s, 3H), 8.54 (s, 1H), 8.28-8.22 (m, 2H),8.14 (d, 1H, J=8.8 Hz), 7.95 (s, 1H), 7.83 (d, 1H, J=6.9 Hz), 7.54 (d,1H, J=8.9 Hz), 7.47-7.44 (m, 2H), 3.18 (br. s, 6H), 3.07 (br. s, 6H); MS(ESI) m/z 495 (M+H)⁺. Anal. calcd for C₂₆H₂₅SF₃N₆Ox2.0 HClx1.0H₂Ox0.3CH₂Cl₂: C, 51.70; H, 4.88; N, 13.76; Cl, 15.09. Found: C, 51.86; H,4.95; N, 13.32; Cl, 14.98.

EXAMPLE CC-15-{2-[3-(Piperazin-1-yl-trifluoromethyl-phenylcarbamoyl)-phenyl]-ethyl}-nicotinamideDihydrochloride

[0562]

[0563] (a) 5-Triethylsilanylethynyl-nicotinic acid methyl ester, CC-1a,was prepared in the manner similar to that described in example AA-1,step (b), except 5-bromo-nicotinic acid methyl ester was used in placeof N-(5-bromo-pyridin-2-yl)-acetamide, AA-1a: HPLC R_(t) 20.1 min.; TLCR_(f) 0.4 (20% ethyl acetate-cyclohexane); ¹H NMR (DMSO-d₆, 300 MHz) δ9.04 (d, 1H, J=2.0 Hz), 8.88 (d, 1H, J=2.0 Hz), 8.25 (t, 1H, J=2.1 Hz),3.90 (s, 3H), 1.02 (t, 9H, J=8.1 Hz), 0.70 (q, 6H, J=7.6 Hz).

[0564] (b) 5-Ethynyl-nicotinic acid methyl ester, CC-1b, was prepared inthe manner similar to that described in example AA-1, step (c), except5-triethylsilanylethynyl-nicotinic acid methyl ester, CC-1a, was used inplace of N-(5-triethylsilanylethynyl-pyridin-2-yl)-acetamide, AA-1b:HPLC R_(t) 9.3 min.; TLC R_(f) 0.2 (20% ethyl acetate-cyclohexane); ¹HNMR (DMSO-d₆, 300 MHz) δ 9.06 (s, 1H), 8.91 (s 1H), 8.30 (s, 1H), 4.58(s, 1H), 3.90 (s, 3H).

[0565] (c)4-({2-[3-(5-Methoxycarbonyl-pyridin-3-ylethynyl)-phenyl]-2-oxo-ethyl}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, CC-1c, was prepared in the manner similar to thatdescribed in example AA-1, step (g), except 5-ethynyl-nicotinic acidmethyl ester, CC-1b, was used instead ofN-(5-ethynyl-pyridin-2-yl)-acetamide, AA-1c: HPLC R_(t) 19.5 min.; TLCR_(f) 0.3 (30% ethyl acetate-cyclohexane); ¹H NMR (DMSO-d₆, 300 MHz) δ10.58 (s, 1H), 9.10 (d, 1H, J=2.0 Hz), 9.04 (d, 1H, J=2.0 Hz), 8.45 (t,1H, J=2.1 Hz), 8.24 (s, 1H), 8.18 (d, 1H, J=2.3 Hz), 8.09-8.03 (m, 2H),7.86 (d, 1H, J=7.8 Hz), 7.68-7.59 (m, 2H), 3.93 (s, 3H), 3.44 (br. s,4H), 2.82-2.79 (m, 4H), 1.41 (s, 9H).

[0566] (d) To a solution of4-({2-[3-(5-methoxycarbonyl-pyridin-3-ylethynyl)-phenyl]-2-oxo-ethyl}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, CC-1c, (846 mg, 1.4 mmol, 1.0 eq) in isopropylalcohol (90 mL) was added aqueous sodium hydroxide (4.2 mL, 1.0 M, 4.2mmol, 3.0 eq). The resultant clear solution was warmed to 50° C. for 5h. The solvent was removed under reduced pressure and the crude productwas dissolved in ethyl acetate, which was sequentially washed withaqueous sodium citrate (0.5 M, pH 4.5) and brine. The organic layer wasdried over magnesium sulfate, filtered and concentrated under reducedpressure to give4-({2-[3-(5-carboxy-pyridin-3-ylethynyl)-phenyl]-2-oxo-ethyl}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, CC-1d, as a white solid (800 mg, 96%): ¹H NMR(DMSO-d₆, 300 MHz) δ 10.59 (s, 1H), 9.08 (d, 1H, J=2.0 Hz), 9.00 (d, 1H,J=2.0 Hz), 8.42 (t, 1H, J=2.1 Hz), 8.24 (s, 1H), 8.18 (d, 1H, J=2.4 Hz),8.09-8.02 (m, 2H), 7.88-7.85 (m, 1H), 7.68-7.59 (m, 2H), 3.44 (br. s,4H), 2.81-2.78 (m, 4H), 1.43 (s, 9H).

[0567] (e)4-[(2-{3-[2-(5-Carboxy-pyridin-3-yl)-ethyl]-phenyl}-2-oxo-ethyl)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, CC-1e, was prepared in the manner similar to thatdescribed in example AA-1, step (h), except4-({2-[3-(5-carboxy-pyridin-3-ylethynyl)-phenyl]-2-oxo-ethyl}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, CC-1d, was used instead of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1g: HPLC (TFA buffered method) R_(t) 16.4min.; TLC R_(f) 0.3 (3% methanol-dichloromethane w/ 0.1% acetic acid);¹H NMR (DMSO-d₆, 300 MHz) δ 10.47 (s, 1H), 8.89 (s, 1H), 8.57 (s, 1H),8.17-8.15 (m, 2H), 8.08-8.05 (m, 1H), 7.88 (s, 1H), 7.81-7.79 (m, 1H),7.58 (d, 1H, J=8.8 Hz), 7.46-7.44 (m, 2H), 3.01 (s, 5H), 2.79 (m, 5H),1.43 (s, 9H); MS (ESI) m/z 597 (M−H)⁻.

[0568] (f) To a solution of4-[(2-{3-[2-(5-carboxy-pyridin-3-yl)-ethyl]-phenyl}-2-oxo-ethyl)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, CC-1e, (250 mg, 0.42 mmol, 1.0 eq) in dioxane (9mL) was added a solution of 1,3-dicyclohexylcarbodiimide (87 mg, 0.42mmol, 1.0 eq) and N-hydroxysuccinimide (48 mg, 0.42 mmol, 1.0 eq) indioxane (1 mL). The cloudy reaction mixture was sequentially stirred for18 h, passed through a teflon filter (0.45 micron pore size), and thesolvent removed under reduced pressure to give a white semi-solid (346mg). To the crude product in dioxane (8 mL) was added triethylamine(0.23 mL, 1.68 mmol, 4.0 eq) and 1,2-diaminomethane dihydrochloride (50mg, 0.42 mmol, 1.0 eq) in a minimal amount of water. The white slurrywas stirred for 4 h at room temperature. The solvent was removed underreduced pressure and the crude product dissolved in ethyl acetate, whichwas sequentially washed with water and brine. The organic layer wasdried over magnesium sulfate, filtered and concentrated under reducedpressure to give a yellow solid (360 mg). The crude product was purifiedby radial chromatography over silica gel, which was eluted with 3-9%methanol-dichloromethane, to give4-[(2-{3-[2-(5-carbamoyl-pyridin-3-yl)-ethyl]-phenyl}-2-oxo-ethyl)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, CC-1f, as a white solid (150 mg, 60%): HPLC R_(t)15.4 min.; TLC R_(f) 0.5 (4% methanol-dichloromethane); ¹H NMR (DMSO-d₆,300 MHz) δ 10.45 (s, 1H), 8.68 (d, 1H, J=1.8 Hz), 8.56 (d, 1H, J=1.8Hz), 8.17-8.04 (m, 3H), 7.87-7.79 (m, 1H), 7.61-7.58 (m, 2H), 7.47-7.45(m, 2H), 5.76 (s, 2H), 3.44 (s, 4H), 3.02 (m, 4H), 2.80 (s, 4H), 1.43(s, 9H); MS (ESI) m/z 598 (M+H)⁺.

[0569] (g)5-(2-{3-[2-(Piperazin-1-yl-trifluoromethyl-phenyl)-ethanoyl]-phenyl}-ethyl)-nicotinamidedihydrochloride, CC-1, was prepared in the manner similar to thatdescribed in example AA-1, step (i), except4-[(2-{3-[2-(5-carbamoyl-pyridin-3-yl)-ethyl]-phenyl}-2-oxo-ethyl)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, CC-1f, was used in place of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1h: HPLC R_(t) 9.7 min.; ¹H NMR (DMSO-d₆, 300MHz) δ 10.56 (s, 1H), 9.13 (br. s, 1H), 9.00 (d, 1H, J=2.0 Hz), 8.75 (d,1H, J=1.9 Hz), 8.49 (s, 1H), 8.33 (s, 1H), 8.22 (d, 1H, J=2.5 Hz), 8.13(dd, 1H, J=8.8, 2.2 Hz), 7.91 (s, 1H), 7.83-7.79 (m, 2H), 7.56 (d, 1H,J=8.7 Hz), 7.48-7.45 (m, 2H), 3.13 (s, 4H), 3.07 (m, 8H); MS (ESI) m/z498 (M+H)⁺. Anal. calcd for C₂₆H₂₆F₃N₅O₂x 2.0 HClx0.5H₂O: C, 53.89; H,5.04; N, 12.09; Cl, 12.24. Found: C, 53.99; H, 5.19; N, 11.46; Cl,11.79.

EXAMPLE CC-25-{2-[3-(Piperazin-1-yl-trifluoromethyl-phenylcarbamoyl)-phenyl]-ethyl}-NicotinicAcid Methyl Ester Dihydrochloride

[0570]

[0571] (a) To a solution of4-[(2-{3-[2-(5-carboxy-pyridin-3-yl)-ethyl]-phenyl}-2-oxo-ethyl)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, CC-1e, (100 mg, 0.17 mmol, 1.0 eq.) in methanol(4 mL) and toluene (4 mL) was added a solution of(trimethylsilyl)diazomethane (0.45 mL, 2.0 M, 0.90 mmol, 5.3 eq). Thelight yellow solution was stirred for 18 h. The solvent was removedunder reduced pressure and the crude product was dissolved in ethylacetate, which was sequentially washed with aqueous 5% sodiumbicarbonate and brine. The organic layer was dried over magnesiumsulfate, filtered and concentrated under reduced pressure to give aclear residue (105 mg). The crude product was purified by radialchromatography over silica gel, which was eluted with 2%methanol-dichloromethane, to give4-{[(1-{3-[2-(5-methoxycarbonyl-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, CC-2a, as a white solid (74 mg, 71%): HPLC R_(t)18.1 min.; TLC R_(f) 0.6 (3% methanol-dichloromethane w/ 0.1% aceticacid); ¹H NMR (DMSO-d₆, 300 MHz) δ 10.42 (s, 1H), 8.92 (d, 1H, J=1.8Hz), 8.69 (d, 1H, J=2.0 Hz), 8.21 (s, 1H), 8.16 (d, 1H, J=2.2 Hz),8.07-8.04 (m, 1H), 7.86 (s, 1H), 7.81-7.79 (m, 1H), 7.60 (d, 1H, J=8.2Hz), 7.48-7.45 (m, 2H), 3.88 (s, 3H), 3.44 (br. s, 4H), 3.04 (s, 4H),2.80 (t, 4H, J=4.3 Hz), 1.43 (s, 9H); MS (ESI) m/z 613 (M+H)⁺.

[0572] (b)5-{2-[3-(Piperazin-1-yl-trifluoromethyl-phenylcarbamoyl)-phenyl]-ethyl}-nicotinicacid methyl ester dihydrochloride, CC-2, was prepared in the mannersimilar to that described in example AA-1, step (i), except,4-{[(1-{3-[2-(5-methoxycarbonyl-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, CC-2a, was used in place of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1h: HPLC R_(t) 12.7 min.; ¹H NMR (DMSO-d₆, 300MHz) δ 10.58 (s, 1H), 9.33 (br. s, 2H), 9.00 (s, 1H), 8.80 (s, 1H), 8.38(s, 1H), 8.22 (s, 1H), 8.14 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.84-7.82(m, 1H), 7.56 (d, 1H, J=8.6 Hz), 7.48-7.42 (m, 2H), 3.90 (s, 3H), 3.16(s, 4H), 3.08 (s, 8H); MS (ESI) m/z 513 (M+H)⁺. Anal. calcd forC₂₇H₂₇F₃N₄O₃x2.0HClx0.5H₂Ox 0.5 ethyl acetate: C, 54.55; H, 5.37; N,8.77. Found: C, 54.47; H, 5.45; N, 8.71.

EXAMPLE DD-14-Fluoro-3-[2-(3H-imidazo[4,5-b]pyridin-6-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamideDihydrochloride

[0573]

[0574] (a)4-({[1-(4-Fluoro-3-hydroxy-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, DD-1a, was prepared in a similar manner to thatdescribed in example M-1, step (e), except4-({[1-(3-acetoxy-4-fluoro-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester was used instead of acetic acid3-(2-methyl-quinolin-6-ylcarbamoyl)-phenyl ester, M-1d: HPLC R_(t) 16.2min.; TLC R_(f) 0.3 (30% ethyl acetate-cyclohexane); ¹H NMR (DMSO-d₆,300 MHz) δ 10.37 (s, 1H), 10.22 (s, 1H), 8.14 (d, 2H, J=2.4 Hz), 8.00(dd, 1H, J=8.6, 2.0 Hz), 7.58-7.53 (m, 3H), 7.47-7.42 (m, 1H), 7.30 (dd,1H, J=11.0, 8.6 Hz), 3.43 (br. s, 4H), 2.79 (t, 4H, J=4.8 Hz), 1.42 (s,9H); MS (ESI) m/z 484 (M+H)⁺.

[0575] (b) To a solution of4-({[1-(4-fluoro-3-hydroxy-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, DD-1a, (900 mg, 1.86 mmol, 1.0 eq), in dioxane(40 mL) was added triethylamine (0.90 mL, 6.5 mmol, 3.0 eq) and1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide(1.1 g, 3.0 mmol, 1.4 eq). The clear solution was stirred for 18 h. Thesolvent was removed under reduced pressure and the resultant oil waspassed through a silica plug, which was eluted with ethyl acetate togive an amber oil (2.0 g). The crude product was purified by radialchromatography over silica gel, which was eluted with 15-25% ethylacetate-cyclohexane, to give4-({[1-(4-fluoro-3-trifluoromethanesulfonyloxy-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, DD-1b, as a white solid (1.0 g, 91%): HPLC R_(t)19.9 min.; TLC R_(f) 0.5 (30% ethyl acetate-cyclohexane); ¹H NMR(DMSO-d₆, 300 MHz) δ 10.61 (s, 1H), 8.25-8.22 (m, 1H), 8.12 (d, 1H,J=2.4 Hz), 8.02 (dd, 1H, J=8.8, 2.2 Hz), 7.86-7.80 (m, 1H), 7.60 (d, 1H,J=8.7 Hz), 7.30-7.25 (m, 1H), 3.44 (br. s, 4H), 2.80 (t, 4H, J=4.7 Hz),1.43 (s, 9H); MS (ESI) m/z 638 (M+Na)⁺.

[0576] (c)4-[({1-[4-Fluoro-3-(3H-imidazo[4,5-b]pyridin-6-ylethynyl)-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, DD-1c, was prepared in the manner similar to thatdescribed in example AA-1, step (g), except6-ethynyl-3H-[4,5-b]pyridine, BB-1e, was used instead ofN-(5-ethynyl-pyridin-2-yl)-acetamide, AA-1 c, and4-({[1-(4-fluoro-3-trifluoromethanesulfonyloxy-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, DD-1b, was used instead of4-({[1-(3-iodo-phenyl)-methanoyl]-amino}-trifluoromethyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester, AA-1f: HPLC R_(t) 16.3 min.; TLC R_(f) 0.3 (4%methanol-chloroform w/ 0.1% ammonium hydroxide); ¹H NMR (DMSO-d₆, 300MHz) δ 13.39, 12.93 (2 br. s, 1H), 10.56 (s, 1H), 8.58-8.55 (m, 3H),8.33 (s, 1H), 8.16 (s, 1H), 8.07-8.05 (m, 2H), 7.61-7.52 (m, 2H), 3.44(br. s, 4H), 2.80 (br. s, 4H), 1.43 (s, 9H); MS (ESI) m/z 609 (M+H)⁺.

[0577] (d)4-{[(1-{4-Fluoro-3-[2-(3H-imidazo[4,5-b]pyridin-6-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, DD-1d, was prepared in the manner similar to thatdescribed in example AA-1, step (h), except4-[({1-[4-fluoro-3-(3H-imidazo[4,5-b]pyridin-6-ylethynyl)-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, DD-1c, was used instead of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1 g: HPLC R_(t) 15.7 min.; TLC R_(f) 0.4 (6%methanol-chloroform w/ 0.1% ammonium hydroxide); ¹H NMR (DMSO-d₆, 300MHz) δ 10.43 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.13 (d, 1H, J=8.8Hz), 8.05-7.97 (m, 2H), 7.91-7.86 (m, 2H), 7.60 (d, 1H, J=8.8 Hz),7.34-7.28 (m, 1H), 3.44 (br. s, 4H), 3.08-3.06 (m, 4H), 2.80 (t, 4H,J=4.6 Hz), 1.43 (s, 9H); MS (ESI) m/z 613 (M+H)⁺.

[0578] (e)4-Fluoro-3-[2-(3H-imidazo[4,5-b]pyridin-6-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride, DD-1, was prepared in the manner similar to thatdescribed in example AA-1, step (i), except4-{[(1-{4-fluoro-3-[2-(3H-[4,5-b]pyridin-6-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, DD-1d, was used in place of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1h: HPLC R, 10.5 min.; ¹H NMR (DMSO-d₆, 300MHz) δ 10.68 (s, 1H), 9.36 (br. s, 3H), 8.55 (s, 1H), 8.26 (d, 2H, J=9.8Hz), 8.12 (t, 2H, J=8.2 Hz), 7.93 (br. s, 1H), 7.56 (d, 1H, J=8.7 Hz),7.30 (t, 1H, J=9.1 Hz), 3.16 (br. s, 6H), 3.08 (m, 6H); MS (ESI) m/z 513(M+H)⁺. Anal. calcd for C₂₆H₂₄F₄N₆Ox2.0 HCl: C, 52.14; H, 4.63; N,14.03; Cl, 11.84. Found: C, 52.54; H, 4.73; N, 13.41; Cl, 11.44.

EXAMPLE EE-14-Fluoro-3-(5-furan-2-yl-pyridin-3-ylmethoxy)-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamideDihydrochloride

[0579]

[0580] (a) To a solution of4-[({1-[3-(5-bromo-pyridin-3-ylmethoxy)-4-fluoro-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, R-25c, (80 mg, 0.12 mmol, 1.0 eq) in dioxane (3mL) was added tributyl-furan-2-yl-stannane (0.05 mL, 0.14 mmol, 1.2 eq)and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.01 mmol, 10 mol%). The light yellow solution was warmed to 95° C. for 18 h. The solventwas removed under reduced pressure and the crude product was dissolvedin ethyl acetate, which was sequentially washed with aqueous 10%potassium fluoride, water and brine. The organic layer was dried overmagnesium sulfate, filtered and concentrated under reduced pressure togive a clear oil (127 mg). The crude product was purified by radialchromatography over silica gel, which was eluted with 1-3%methanol-dichloromethane, to give4-[({1-[4-fluoro-3-(5-furan-2-yl-pyridin-3-ylmethoxy)-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, EE-1a, as a white solid (66 mg, 86%): HPLC R_(t)18.9 min.; TLC R_(f) 0.4 (2% methanol-dichloromethane); ¹H NMR (DMSO-d₆,300 MHz) δ 10.44 (s, 1H), 8.96 (d, 1H, J=2.1 Hz), 8.62 (d, 1H, J=1.9Hz), 8.19 (t, 1H, J=2.0 Hz), 8.14 (d, 1H, J=2.3 Hz), 8.03 (dd, 1H,J=8.6, 2.2 Hz), 7.89 (dd, 1H, J=8.3, 1.9 Hz), 7.86 (d, 1H, J=1.6 Hz),7.69-7.65 (m, 1H), 7.60 (d, 1H, J=8.8 Hz), 7.44 (dd, 1H, J=11.0, 8.6Hz), 7.16 (d, 1H, J=3.3 Hz), 6.67 (dd, 1H, J=3.4, 1.8 Hz), 5.38 (s, 2H),3.44 (br. s, 4H), 2.80 (t, 4H, J=4.7 Hz), 1.43 (s, 9H); MS (ESI) m/z 641(M+H)⁺.

[0581] (b)4-Fluoro-3-(5-furan-2-yl-pyridin-3-ylmethoxy)-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride, EE-1, was prepared in the manner similar to thatdescribed in example AA-1, step (i), except4-[({1-[4-fluoro-3-(5-furan-2-yl-pyridin-3-ylmethoxy)-phenyl]-methanoyl}-amino)-trifluoromethyl-phenyl]-piperazine-1-carboxylicacid tert-butyl ester, EE-1a, was used in place of4-{[(1-{3-[2-(6-acetylamino-pyridin-3-yl)-ethyl]-phenyl}-methanoyl)-amino]-trifluoromethyl-phenyl}-piperazine-1-carboxylicacid tert-butyl ester, AA-1 h: HPLC R_(t) 14.2 min.; ¹H NMR (DMSO-d₆,300 MHz) δ 10.66 (s, 1H), 9.16 (br. s, 2H), 9.03 (s, 1H), 8.70 (s, 1H),8.37 (s, 1H), 8.21 (d, 1H, J=2.0 Hz), 8.14 (d, 1H, J=8.9 Hz), 7.99 (d,1H, J=7.0 Hz), 7.89 (s, 1H), 7.72-7.69 (m, 1H), 7.56 (d, 1H, J=8.5 Hz),7.44 (dd, 1H, J=10.8, 8.7 Hz), 7.24 (d, 1H, J=3.3 Hz), 6.69 (d, 1H,J=1.5 Hz), 5.45 (s, 2H), 3.17 (s, 4H), 3.07 (s, 4H); MS (ESI) m/z 541(M+H)⁺. Anal. calcd for C₂₈H₂₄F₄N₄O₃x2.0HClx1.0H₂O: C, 53.26; H, 4.47;N, 8.87; Cl, 11.23. Found: C, 53.27; H, 4.25; N, 8.56; Cl, 11.48.

[0582] The exemplary compounds described above may be tested for theiractivity as described below.

[0583] Biological Testing: Enzyme Assays

[0584] The stimulation of cell proliferation by growth factors such asVEFG, FGF, and others is dependent upon their induction ofautophosphorylation of each of their respective receptor's tyrosinekinases. Therefore, the ability of a protein kinase inhibitor to blockcellular proliferation induced by these growth factors is directlycorrelated with its ability to block receptor autophosphorylation. Tomeasure the protein kinase inhibition activity of the compounds, thefollowing constructs were devised.

[0585] VEGF-R2 Construct for Assay: A construct (VEGF-R2Δ50) of thecytosolic domain of human vascular endothelial growth factor receptor 2(VEGF-R2) lacking the 50 central residues of the 68 residues of thekinase insert domain was expressed in a baculovirus/insect cell system.Of the 1356 residues of full-length VEGF-R2, VEGF-R2Δ50 containsresidues 806-939 and 990-1171, and also one point mutation (E990V)within the kinase insert domain relative to wild-type VEGF-R2. Seecommonly assigned, co-pending U.S. patent application Ser. No.09/390,326, filed Sep. 7, 1999, incorporated by reference herein, fordiscussion of VEGF constructs and expression systems.Autophosphorylation of the purified construct was performed byincubation of the enzyme at a concentration of 4 μM in the presence of 3mM ATP and 40 mM MgCl₂ in 100 mM Hepes, pH 7.5, containing 5% glyceroland 5 mM DTT, at 4° C. for 2 h. After autophosphorylation, thisconstruct has been shown to possess catalytic activity essentiallyequivalent to the wild-type autophosphorylated kinase domain construct.See Parast et al., Biochemistry, 37, 16788-16801 (1998).

[0586] FGF-R1 Construct for Assay: The intracellular kinase domain ofhuman FGF-R1 was expressed using the baculovirus vector expressionsystem starting from the endogenous methionine residue 456 to glutamate766, according to the residue numbering system of Mohammadi et al., Mol.Cell. Biol., 16, 977-989 (1996). In addition, the construct also has thefollowing 3 amino acid substitutions: MA57V, C488A, and C584S.

[0587] LCK Construct for Assay: The LCK tyrosine kinase was expressed ininsect cells as an N-terminal deletion starting from amino acid residue223 to the end of the protein at residue 509, with the following twoamino acid substitutions at the N-terminus: P233M and C224D.

[0588] CHK-1 Construct for Assay: C-terminally His-tagged full-lengthhuman CHK-1 (FL-CHK-1) was expressed using the baculovirus/insect cellsystem. It contains 6 histidine residues (6xHis-tag) at the C-terminusof the 476 amino acid human CHK-1. The protein was purified byconventional chromatographic techniques.

[0589] Catalytically active truncations of CHK-1 may be exchanged forthe full length CHK-1 protein. A preferred truncation comprises thekinase domain of CHK-1, which begins between amino acid residues 1 and16 and terminates between amino acid residues 265 and 291. See commonlyassigned, co-pending U.S. patent application Ser. No. 09/460,421, filedDec. 14, 1999, incorporated by reference herein, for discussion of suchalternate CHK-1 constructs and expression systems.

[0590] CDK2/Cyclin A Construct for Assay: CDK2 was purified usingpublished methodology (Rosenblatt et al., J. Mol. Biol., 230, 1317-1319(1993)) from insect cells that had been infected with a baculovirusexpression vector. Cyclin A was purified from E. coli cells expressingfull-length recombinant cyclin A, and a truncated cyclin A construct wasgenerated by limited proteolysis and purified as described previously(Jeffrey et al., Nature, 376, 313-320 (1995)).

[0591] CDK4/Cyclin D Construct for Assay: A complex of human CDK4 andcyclin D3, or a complex of cyclin D1 and a fusion protein of human CDK4and glutathione-S-transferase (GST-CDK4), was purified using traditionalbiochemical chromatographic techniques from insect cells that had beenco-infected with the corresponding baculovirus expression vectors.

[0592] TEK Construct for Assay: The intracellular kinase domain(residues 775 to 1124, with methionine added at the N-terminus) of humanTEK/Tie-2 was expressed using the baculovirus vector expression system.For assay purposes, the enzyme was autophosphorylated prior to use byincubation overnight at 4° C., at 10 μM enzyme concentration, with 4 mMATP, 40 mM MgCl₂, and 5 mM DTT in 200 mM Hepes buffer at ph 7.5, in90:10 water:glycerol.

[0593] VEGF-R2 Assay

[0594] Coupled Spectrophotometric (FLVK-P) Assay

[0595] The production of ADP from ATP that accompanies phosphoryltransfer was coupled to oxidation of NADH using phosphoenolpyruvate(PEP) and a system having pyruvate kinase (PK) and lactic dehydrogenase(LDH). The oxidation of NADH was monitored by following the decrease ofabsorbance at 340 nm (e₃₄₀=6.22 cm⁻¹ mM⁻¹) using a Beckman DU 650spectrophotometer. Assay conditions for phosphorylated VEGF-R2Δ50(indicated as FLVK-P in the tables below) were the following: 1 mM PEP;250 μM NADH; 50 units of LDH/mL; 20 units of PK/mL; 5 mM DTT; 5.1 mMpoly(E₄Y₁); 1 mM ATP; and 25 mM MgCl₂ in 200 mM Hepes, pH 7.5. Assayconditions for unphosphorylated VEGF-R2Δ50 (indicated as FLVK in thetables) were the following: 1 mM PEP; 250 uM NADH; 50 units of LDH/mL;20 units of PK/mL; 5 mM DTT; 20 mM poly(E₄Y₁); 3 mM ATP; and 60 mM MgCl₂and 2 mM MnCl₂ in 200 mM Hepes, pH 7.5. Assays were initiated with 5 to40 nM of enzyme. K_(i) values were determined by measuring enzymeactivity in the presence of varying concentrations of test compounds.The data were analyzed using Enzyme Kinetic and Kaleidagraph software.

[0596] ELISA Assay

[0597] Formation of phosphogastrin was monitored using biotinylatedgastrin peptide (1-17) as substrate. Biotinylated phosphogastrin wasimmobilized using streptavidin coated 96-well microtiter plates followedby detection using anti-phosphotyrosine-antibody conjugated tohorseradish peroxidase. The activity of horseradish peroxidase wasmonitored using 2,2′-[3-ethylbenzathiazoline sulfonate(6)] diammoniumsalt (ABTS). Typical assay solutions contained: 2 μM biotinylatedgastrin peptide; 5 mM DTT; 20 μM ATP; 26 mM MgCl₂; and 2 mM MnCl₂ in 200mM Hepes, pH 7.5. The assay was initiated with 0.8 nM of phosphorylatedVEGF-R2Δ50. Horseradish peroxidase activity was assayed using ABTS, 10mM. The horseradish peroxidase reaction was quenched by addition of acid(H₂SO₄), followed by absorbance reading at 405 nm. K_(i) values weredetermined by measuring enzyme activity in the presence of varyingconcentrations of test compounds. The data were analyzed using EnzymeKinetic and Kaleidagraph software.

[0598] FGF-R Assay

[0599] The spectrophotometric assay was carried out as described abovefor VEGF-R2, except for the following changes in concentration: FGF-R=50nM, ATP=2 mM, and poly(E4Y1)=15 mM.

[0600] LCK Assay

[0601] The spectrophotometric assay was carried out as described abovefor VEGF-R2, except for the following changes in concentration: LCK=60nM, MgCl₂=40 nM, poly(E4Y1)=20 mM.

[0602] CHK-1 Assay

[0603] The production of ADP from ATP that accompanies phosphoryltransfer to the synthetic substrate peptide Syntide-2 (PLARTLSVAGLPGKK)was coupled to oxidation of NADH using phosphoenolpyruvate (PEP) throughthe actions of pyruvate kinase (PK) and lactic dehydrogenase (LDH). Theoxidation of NADH was monitored by following the decrease of absorbanceat 340 nm (∈340=6.22 cm⁻¹ mM⁻¹) using a HP8452 spectrophotometer.Typical reaction solutions contained: 4 mN PEP; 0.15 mM NADH; 28 unitsof LDH/ml; 16 units of PK/ml; 3 mM DTT; 0.125 mM Syntide-2; 0.15 mM ATP;25 mM MgCl₂ in 50 mM TRIS, pH 7.5; and 400 mM NaCl. Assays wereinitiated with 10 nM of FL-CHK-1. K_(i) values were determined bymeasuring initial enzyme activity in the presence of varyingconcentrations of test compounds. The data were analyzed using EnzymeKinetic and Kaleidagraph software.

[0604] CDK2/Cyclin A and CDK4/Cyclin D Assays

[0605] Cyclin-dependent kinase activity was measured by quantifying theenzyme-catalyzed, time-dependent incorporation of radioactive phosphatefrom [³²P]ATP into a recombinant fragment of the retinoblastoma protein.Unless noted otherwise, assays were performed in 96-well plates in atotal volume of 50 μL, in the presence of 10 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid]) (pH 7.4), 10mM MgCl₂, 25 μM adenosine triphosphate (ATP), 1 mg/mL ovalbumin, 5 μg/μLleupeptin, 1 mM dithiothreitol, 10 mM β-glycerophosphate, 0.1 mM sodiumvanadate, 1 mM sodium fluoride, 2.5 mM ethylene glycol-bis(β-aminoethylether)-N,N,N′N′-tetraacetic acid (EGTA), 2% (v/v) dimethylsulfoxide, and0.03-0.2 μCi [³²P]ATP. The substrate (0.3-0.5 μg) was purifiedrecombinant retinoblastoma protein fragment (Rb) (residues 386-928 ofthe native retinoblastoma protein; 62.3 kDa, containing the majority ofthe phosphorylation sites found in the native 106-kDa protein, as wellas a tag of six histidine residues for ease of purification). Reactionswere initiated with CDK2 (150 nM CDK2/Cyclin A complex) or CDK4 (50 nMCDK4/Cyclin D3 complex), incubated at 30° C., and terminated after 20minutes by the addition of ethylenediaminetetraacetic acid (EDTA) to 250mM. The phosphorylated substrate was then captured on a nitrocellulosemembrane using a 96-well filtration manifold, and unincorporatedradioactivity was removed by repeated washing with 0.85% phosphoricacid. Radioactivity was quantified by exposing the dried nitrocellulosemembranes to a phosphorimager. Apparent K_(i) values were measured byassaying enzyme activity in the presence of different compoundconcentrations and subtracting the background radioactivity measured inthe absence of enzyme. The kinetic parameters (kcat, Km for ATP) weremeasured for each enzyme under the usual assay conditions by determiningthe dependence of initial rates on ATP concentration. The data were fitto an equation for competitive inhibition using Kaleidagraph (SynergySoftware), or were fit to an equation for competitive tight-bindinginhibition using the software KineTic (BioKin, Ltd.). Measured K_(i)values for known inhibitors against CDK4 and CDK2 agreed with publishedIC₅₀ values. The specific activity of CDK4 was the same whethercomplexed to full-length cyclin D3 or the truncated Cyclin D3 construct;both complexes also yielded very similar K_(i) values for selectedinhibitors.

[0606] TEK/Tie-2 Assay

[0607] The spectrophotometric assay was carried out as described abovefor VEGF-R2, except for the following changes in concentration:TEK/Tie-2=200 nM, MgCl₂=40 mM, and ATP=2 mM.

[0608] HUVEC Proliferation Assay

[0609] This assay determines the ability of a test compound to inhibitthe growth factor-stimulated proliferation of human umbilical veinendothelial cells (“HUVEC”). HUVEC cells (passage 3-4, Clonetics, Corp.)were thawed into EGM2 culture medium (Clonetics Corp) in T75 flasks.Fresh EGM2 medium was added to the flasks 24 hours later. Four or fivedays later, cells were exposed to another culture medium (F12K mediumsupplemented with 10% fetal bovine serum (FBS), 60 μg/ml endothelialcell growth supplement (ECGS), and 0.1 mg/ml heparin).Exponentially-growing HUVEC cells were used in experiments thereafter.Ten to twelve thousand HUVEC cells were plated in 96-well dishes in 100μl of rich, culture medium (described above). The cells were allowed toattach for 24 hours in this medium. The medium was then removed byaspiration and 105 μl of starvation media (F12K+1% FBS) was added toeach well. After 24 hours, 15 μl of test agent dissolved in 1% DMSO instarvation medium or this vehicle alone was added into each treatmentwell; the final DMSO concentration was 0.1%. One hour later, 30 μl ofVEGF (30 ng/ml) in starvation media was added to all wells except thosecontaining untreated controls; the final VEGF concentration was 6 ng/ml.Cellular proliferation was quantified 72 hours later by MTT dyereduction, at which time cells were exposed for 4 hours MTT (PromegaCorp.). Dye reduction was stopped by addition of a stop solution(Promega Corp.) and absorbance at 595 λ was determined on a 96-wellspectrophotometer plate reader.

[0610] Cancer Cell Proliferation (MV522) Assay

[0611] The protocol for assessing cellular proliferation in cancer cellsis similar to that used for assessments in HUVEC cells. Two thousandlung cancer cells (line MV522, acquired from American Tissue CulturalCollection) were seeded in growth media (RPMI1640 medium supplementedwith 2 mM glutamine and 10% FBS). Cells are allowed to attach for 1 dayprior to addition of test agents and/or vehicles. Cells are treatedsimultaneously with the same test agents used in the HUVEC assay.Cellular proliferation is quantified by MTT dye reduction assay 72 hoursafter exposure to test agents. The total length of the assay is 4 daysvs. 5 for HUVEC cells because MV522 cells are not exposed to starvationmedium.

[0612] The results of the testing of the compounds using various assaysare summarized in the table below, where a notation of “% @” indicatesthe percent inhibition at the stated concentration, “NI” indicates noinhibition, “slow-binding kinetics” indicates that curvature in theprogress curves in the enzyme assay precluded the determination ofrates, and “NT” indicates compounds “not tested” for a particularactivity. Huvec + FLVK-P FLVK LCK- CDK2 CDK4 HUVEC Albumin MV522 Ki Ki PKi CHK-1 FGF-P Ki Ki IC50 IC50 IC50 TEK-P EX # (nM) (nM) (nM) Ki (nM) Ki(nM) (nM) (nM) (nM) (nM) (μM) (μM) A-1 785 NT NT NT NT NT NT NT NT NT NTA-2 100 μM NT NT NT NT NT NT NT NT NT NT A-3 32 4.5 NT NT NT NT NT 240NT >10 NT A-4 13000 NT NT NT NT NT NT NT NT NT NT A-5 8.64 1 37% @ NT NTNT NT 270 NT >10 NT 5 μM A-6 1050 NT NT NT NT NT NT NT NT NT NT A-7 26NT NT NT NT NT NT >700 NT NT NT A-8 3.36 1.9 NT NT NT NT NT 740 NT >10NT B-1 111 25 NT NT 87,000 NT NT NT NT NT NT B-10 NI @ NT NT NT NT NT NTNT NT NT NT 300 μM (ELISA) B-11 NI @ NT NT NT NT NT NT NT NT NT NT 300μM (ELISA) B-12 28 NT NT NT NT NT NT 530 NT >10 NT B-13 NI @ NT NT NT NTNT NT NT NT NT NT 1 mM (ELISA) B-14 NI @ NT NT NT NT NT NT NT NT NT NT490 μM (ELISA) B-15 15.7 NT NT NT NT NT NT 120 NT >10 NT B-16 15 NT 9% @NT NT NT NT 370 NT >10 NT 1 μM B-17 6.95 NT NT NT NT NT NT >700 NT >10NT B-18 5.84 NT NT NT NT NT NT 130 NT >10 NT B-19 42% @ NT NT NT NT NTNT NT NT NT NT 1 μM B-2 1820 NT NT NT NT NT NT NT NT NT NT B-20 26 NT NTNT NT NT NT NT NT NT NT B-21 208 NT NT NT NT NT NT NT NT NT NT B-22 32%@ NT NT NT NT NT NT NT NT NT NT 1 μM B-23 17% @ 1 NT NT NT NT NT NT NTNT NT NT μM B-24 37 NT NT NT NT NT NT NT NT NT NT B-25 26% @ 1 NT NT NTNT NT NT NT NT NT NT μM B-3 406 NT NT NT NT NT NT NT NT NT NT B-4 35000NT NT NT NT NT NT NT NT NT NT B-5 11000 NT NT NT NT NT NT NT NT NT NTB-6 62% @ NT NT NT NT NT NT NT NT NT NT 10 μM (ELISA) B-7 3310 NT NT NTNT NT NT NT NT NT NT B-8 NI @ NT NT NT NT NT NT NT NT NT NT 1 mM (ELISA)B-9 17000 NT NT NT NT NT NT NT NT NT NT C-1 NI @ NT NT NT NT NT NT NT NTNT NT 1 mM (ELISA) C-2 NI @ NT NT NT NT NT NT NT NT NT NT 50 μM (ELISA)C-3 NI @ 5 NT NT NT NT NT NT NT NT NT NT μM (ELISA) D-1 28 NT NT NT NTNT NT 520 NT >10 NT D-2 1640 NT NT NT NT NT NT NT NT NT NT D-3 133 NT NTNT NT NT NT NT NT NT NT E-1 2.21 1.4 85% @ NT 36% at 23% @ 40% @170 >1000 >10 NT 5 μM 5 μM 100 μM 100 μM E-2 4.79 0.95 NT NTNT >100 >100 55 NT >10 NT μM μM F-1 2.36 NT 22% @ NT 11% @ NT NT 710NT >10 NT 1 μM 1 μM F-2 14.7 NT NT NT NT NT NT 650 NT >10 NT F-3 1.010.31 84% @ NT 83% @ NT NT 10 NT >10 NT 1 μM 1 μM F-4 slow- slow- 19% @NT 18% @ NT NT 63 NT 2.6 NT binding binding 1 μM 1 μM kinetics kineticsF-5 NT 0.86 84% @ NT 69% @ NT NT 4.1 17 1.4 56% @ 1 μM 1 μM 1 μM G-10.592 NT 90 NT 81% @ NT NT 10 435 >10 NT 1 μM G-10 2.6 3 48% @ NT 33% @NT NT 5.7 180 5.1 NT 1 μM 1 μM G-11 0.17 0.11 2.5 7% @ 1 19 NI @ 1 16% @4.4 64 5.6 NT μM μM 1 μM G-2 1.78 NT NT NT NT NT NT 120 NT >10 NT G-30.197 NT 11.2 NT 91% @ NT NT 9.8 280 >10 NT 1 μM G-4 0.79 0.1 72 NT 77%@ NT NT 16 NT >10 NT 1 μM G-5 1.86 0.35 69 NT 68% @ NT NT 8.4 NT >10 NT1 μM G-6 1.98 NT 65 NT 74% @ NT NT 12 59 10 NT 1 μM G-7 0.65 0.25 27 NT23 NT NT 17 190 >10 14% @ 1 μM G-8 0.73 0.035 5.8 NT 20 NT NT 12 114 8.762% @ 1 μM G-9 NT 2.5 NT NT NT NT NT NT NT NT NT H-1 1.19 0.19 41% @ NT83% @ NT NT 27 NT >10 NT 1 μM 1 μM I-1 8.84 NT NT NT NT NT NT 220 NT >10NT I-2 16% @ NT NT NT NT NT NT NT NT NT 1 μM J-1 NT 1.6 38% @ NT 61% @NT NT 37 NT NT NT 1 μM 1 μM J-2 NT 0.68 10.5 NT 57 NT NT 26 180 >10 17%@ 1 μM J-3 NT 0.92 44% @ NT 54% @ NT NT 50 NT NT NT 1 μM 1 μM K-1 1.461.6 59 NT 79% @ NT NT 40 >1000 10 NT 1 μM K-10 2.19 0.23 57.7 8% @ 1 2612% @ 17% @ 12 NT 4.6 NT μM 1 μM 1 μM K-11 3.49 NT 82% @ NT 59% @ NT NT37 NT 8.1 NT 1 μM 1 μM K-12 2.96 NT 48% @ NT 70% @ NT NT 27 NT 4.7 NT 1μM 1 μM K-2 138 NT NT NT NT NT NT NT NT NT NT K-3 1.66 3.4 NT 26,000 NI@ 150 NT NT 430 NT >10 NT μM K-4 64 NT NT NT NT NT NT 380 NT >10 NT K-51270 NT NT NT NT NT NT NT NT NT NT K-6 200 NT NT NT NI @ NT NT NT NT NTNT 1 mM K-7 122 NT NT NT NT NT NT NT NT NT NT K-8 707 NT NT NT NT NT NTNT NT NT NT K-9 109 10 NT NT NI @ 600 NT NT NT NT NT NT μM L-1 NT 3% @NT NT NT NT NT NT NT NT NT 50 nM M-1 52 NT NT NT NT NT NT NT NT NT NTN-1 3.74 1.3 160 10% @ 1 12% @ 18% @ 19% @ 38 >1000 >10 NT μM 1 μM 1 μM1 μM N-2 NT 8% @ NT NT NT NT NT >100 NT >10 NT 50 nM O-1 NT 5.5 NT NT NTNT NT >300 NT <3 NT O-2 NT 13% @ NT NT NT NT NT NT NT NT NT 50 nM O-3 NT5.8 NT NT NT NT NT NT NT NT NT P-1 4% @ 50 NT NT NT NT NT NT NT NT NT NTnM Q-1 17% @ 50 NT NT NT NT NT NT 100-300 NT NT NT nM R-1 49% @ 50 NT NTNT NT NT NT NT NT NT NT nM R-10 12.1 6.9 23% @ NT NT NT NT 28 NT >10 NT1 μM R-11 NT slow- 59% @ NT 30% @ 1 NT NT 31 NT NT NT binding 1 μM μM59% @ 50 nM R-12 NT 4.4 45% @ NT 62% @ NT NT 15 NT 5.9 NT 1 μM 1 μM R-13NT 16.5 5% @ NT 7% @ NT NT 19 120 1.8 NT 1 μM 1 μM R-14 NT 3.4 87% @ NT96% @ 1 NT NT 14 345 5.7 NT 1 μM μM R-15 NT 8.8 26% @ NT 41% @ 1 NT NT36 130 3.1 NT 1 μM μM R-16 NT 2.3 NT NT NT NT NT 13 NT 5.6 NT R-17 NT7.4 NT NT NT NT NT 32 NT NT R-18 NT 3.1 NT NT NT NT NT 18 NT >10 NT R-19NT 13.9 NT NT NT NT NT 64 NT 1.7 NT R-2 2.53 NT NT NT NT NT NT 110 NT0.43 NT R-20 NT 19% @ NT NT NT NT NT 155 NT 2.6 NT 50 nM R-3 67% @ 5 NTNT NT NT NT NT 50 NT 9.7 NT μM R-4 9.93 2.4 28% @ NT NT NT NT 88 NT 9.9NT 1 μM R-5 11.2 1.7 NT NT NT NT 89 NT 10 NT R-6 16% @ 5 NT NT NT NT NTNT NT NT NT NT μM R-7 325 NT NT NT NT NT NT NT NT NT NT R-8 4% @ NT NTNT NT NT NT NT NT NT NT 5 μM R-9 9% @ NT NT NT NT NT NT NT NT NT NT 1 μMR-21 NT 42% @ NT NT NT NT NT NT NT NT NT 50 nM R-22 NT 52% @ 13% @ NT21% @ 1 NT NT NT >100 NT NT 50 nM 1 μM μM R-23 NT 50% @ NT NT NT NT NTNT NT NT NT 50 nM R-24 NT 62% @ NT NT NT NT NT NT NT NT NT 50 nM R-25 NT6.6 NT NT NT NT NT NT 155 NT NT S-1 2% @ NT NT NT NT NT NT NT NT NT NT 1μM S-2 28% @ 1 NT NT NT NT NT NT NT NT NT NT μM S-3 8.7 0.76 NT NT NT NTNT 180 NT NT NT S-4 20% @ 50 NT NT NT NT NT NT >300 NT NT NT nM S-5 4.2NT NT NT NT NT NT >300 NT NT NT S-6 6% @ 50 NT NT NT NT NT NT NT NT NTNT nM S-7 NT 19% @ NT NT NT NT NT >300 NT NT NT 50 nM S-8 NT 1.4 NT NTNT NT NT NT NT NT NT T-1 13.6 NT NT NT NT NT NT NT NT NT NT U-1 68 NT NTNT NT NT NT NT NT NT NT U-2 12.4 NT NT NT NT NT NT 100 NT >10 NT V-1 NT2 NT NT NT NT NT NT NT NT NT V-2 13 NT NT NT NT NT NT 180 NT 10 NT V-342% @ NT NT NT NT NT NT NT NT NT NT 1 μM V-4 NT 0.045 22% @ NT 37% @ NTNT 27 >1000 NT 40% @ 1 μM 1 μM 1 μM V-5 NT 1.4 NT NT NT NT NT NT NT NTNT V-6 NT 12% @ NT NT NT NT NT NT NT NT NT 50 nM V-7 NT 2.6 NT NT NT NTNT NT NT NT NT V-8 NT 0% @ NT NT NT NT NT NT NT NT NT 50 nM V-9 NT 22 NTNT NT NT NT NT NT NT NT V-10 NT 16% @ NT NT NT NT NT NT NT NT NT 50 μMV-11 NT 18% @ NT NT NT NT NT NT NT NT NT 50 nM V-12 NT 18% @ NT NT NT NTNT NT NT NT NT 50 nM V-13 NT 17% @ NT NT NT NT NT NT NT NT NT 50 nM V-15NT 30% @ NT NT NT NT NT NT NT NT NT 50 nM W-1 NT 0.12 88% @ NT 67% @ NTNT 23 NT NT NT 1 μM 1 μM W-2 NT 1.5 19% @ NT 18% @ NT NT 120 NT NT NT 1μM 1 μM W-3 NT 0.7 65% @ NT 56% @ NT NT 220 NT NT NT 1 μM 1 μM X-1 NT1.5 59% @ NT 28% @ NT NT 27 330 NT NT 1 μM 1 μM X-2 NT 9.1 NT NT NT NTNT NT NT NT NT X-3 NT 2.2 NT NT NT NT NT 30-100 NT 4.6 NT X-4 NT 4.1 11%@ NT 11% @ NT NT 71 >1000 6.1 NT 1 μM 1 μM X-5 NT 1.3 NT NT NT NT NT 29NT 3.7 NT Y-1 NT 6% @ NT NT NT NT NT >700 NT NT NT 50 nM Y-2 NT NI @ NTNT NT NT NT NT NT NT NT 50 nM Z-1 NI @ NT NT NT NT NT NT NT NT NT NT 5μM AA-1 59% @ 50 2.8 44% @ NT 39% @ NT NT NT 25 NT NT nM 1 μM 1 μM AA-2NT 25 NT NT NT NT NT NT 80 NT NT BB-1 NT 10.8 NT NT NT NT NT NT 940 NTNT CC-1 NT 20% @ NT NT NT NT NT NT NT NT NT 50 nM CC-2 NT 30% @ NT NT NTNT NT NT NT NT NT 50 nM DD-1 NT 5.6 NT NT NT NT NT NT 700 NT NT EE-1 NT3.4 53% @ NT 32% @ NT NT NT 180 NT NT 1 μM 1 μM

[0613] The exemplary compounds described above may be formulated intopharmaceutical compositions according to the following general examples.

EXAMPLE 1 Parenteral Composition

[0614] To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula I is dissolved in DMSO and then mixed with 10 mL of0.9% sterile saline. The mixture is incorporated into a dosage unit formsuitable for administration by injection.

EXAMPLE 2 Oral Composition

[0615] To prepare a pharmaceutical composition for oral delivery, 100 mgof a compound of Formula I is mixed with 750 mg of lactose. The mixtureis incorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

EXAMPLE 3 Intraocular Composition

[0616] To prepare a sustained-release pharmaceutical for intraoculardelivery, a compound of Formula I is suspended in a neutral, isotonicsolution of hyaluronic acid (1.5% conc.) in phosphate buffer (pH 7.4) toform a 1% suspension.

[0617] It is to be understood that the foregoing description isexemplary and explanatory in nature, and is intended to illustrate theinvention and its preferred embodiments. Thus, the scope of theinvention should be understood to be defined not by the foregoingdescription, but by the following claims and their equivalents.

What is claimed:
 1. A compound represented by the Formula I:

wherein: R¹ is a moiety represented by the formula

 where Z is selected from the group consisting of CH and NH, and Q is amoiety such that R¹ is a substituted or unsubstituted monocyclic orbicyclic heteroaryl which has at least two carbon atoms in theheteroaryl ring system; X is selected from the group consisting of CH₂,O, S, and NH; Y is selected from the group consisting of CH₂, O, and S,provided that at least one of X and Y is CH₂, or X and Y together withthe bond there-between form a cyclopropyl; R² and R³ are independentlyselected from the group consisting of hydrogen, methyl, halogen,trifluoromethyl, and cyano; and R⁴ is selected from the group consistingof

 where R⁵ is selected from the group consisting of substituted andunsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, O—R⁷,NR⁸R⁹, C₁-C₈ alkyl, and monocyclic heterocycloalkyl, R⁶ is selected fromthe group consisting of substituted and unsubstituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, alkenyl, O—R⁷, C(O)R⁷, NR⁸R⁹, C₂-C₈ alkyl,and monocyclic heterocycloalkyl, where R⁷ is selected from the groupconsisting of substituted and unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, R⁸ is selected from the groupconsisting of hydrogen, and substituted and unsubstituted alkyl, and R⁹is selected from the group consisting of substituted and unsubstitutedalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or apharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R¹ is a substituted or unsubstituted heteroaryl groupselected from the group consisting of:

X is selected from the group consisting of CH₂, O, and S; Y is selectedfrom the group consisting of CH₂ and S, provided that at least one of Xand Y is CH₂; R² and R³ are independently selected from the groupconsisting of hydrogen, methyl, fluorine, and chlorine, and R⁴ isselected from the group consisting of

 where R⁵ is selected from the group consisting of substituted andunsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, O—R⁷,NR⁸R⁹, C₁-C₈ alkyl and monocyclic heterocycloalkyl, R⁶ is selected fromthe group consisting of substituted and unsubstituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, alkenyl, O—R⁷, C(O)R⁷, NR⁸R⁹, C₂-C₈ alkyl,and monocyclic heterocycloalkyl, where R⁷ is selected from the groupconsisting of substituted and unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, R⁸ is selected from the groupconsisting of hydrogen and substituted and unsubstituted alkyl, and R⁹is selected from the group consisting of substituted and unsubstitutedalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or apharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt thereof.
 3. A compound representedby the Formula II:

wherein: X is selected from the group consisting of CH₂, O, and S; Y isis selected from the group consisting of CH₂ and S, provided that atleast one of X and Y is CH₂; R² and R³ are independently selected fromthe group consisting of hydrogen, methyl, fluorine, and chlorine; R⁴ isselected from the group consisting of

 where R⁵ and R⁶ are each independently selected from the groupconsisting of substituted and unsubstituted aryl and heteroaryl; and R¹⁰is selected from the group consisting of substituted and unsubstitutedalkenyl, aryl, heteroaryl, and HNR⁹, where R⁹ is selected from the groupconsisting of substituted and unsubstituted alkyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl; or a pharmaceutically acceptableprodrug, pharmaceutically active metabolite, or pharmaceuticallyacceptable salt thereof.
 4. A compound according to claim 3, wherein R⁵and R⁶ are each independently selected from the group consisting ofsubstituted and unsubstituted aryl; or a pharmaceutically acceptablesalt, a pharmaceutically acceptable prodrug, or a pharmaceuticallyactive metabolite thereof, or a pharmaceutically acceptable salt of saidmetabolite.
 5. A compound according to claim 3, wherein R⁵ and R⁶ areeach independently selected from the group consisting of substituted andunsubstituted heteroaryl; or a pharmaceutically acceptable salt, apharmaceutically acceptable prodrug, or a pharmaceutically activemetabolite thereof, or a pharmaceutically acceptable salt of saidmetabolite.
 6. A compound represented by the Formula III:

wherein: X is selected from the group consisting of CH₂, O, S, and NH; Yis selected from the group consisting of CH₂, O, and S, provided that atleast one of X and Y is CH₂, or X and Y together with the bondthere-between form a cyclopropyl; R² and R³ are independently selectedfrom the group consisting of hydrogen, methyl, halogen, trifluoromethyl,and cyano; and R⁴ is selected from the group consisting of

 where R⁵ is selected from the group consisting of substituted andunsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, O—R⁷,NR⁸R⁹, C₁-C₈ alkyl, and monocyclic heterocycloalkyl, R⁶ is selected fromthe group consisting of substituted and unsubstituted aryl, heteroaryl,cycloalkyl, heterocycloalkyl, alkenyl, O—R⁷, C(O)R⁷, NR⁸R⁹, C₂-C₈ alkyl,and monocyclic heterocycloalkyl, where R⁷ is selected from the groupconsisting of substituted and unsubstituted alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, R⁸ is selected from the groupconsisting of hydrogen and substituted and unsubstituted alkyl, and R⁹is selected from the group consisting of substituted and unsubstitutedalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or apharmaceutically acceptable prodrug, pharmaceutically active metabolite,or pharmaceutically acceptable salt thereof.
 7. A compound according toclaim 6, wherein: X is selected from the group consisting of CH₂, O, andS; Y is selected from the group consisting of CH₂ and S, provided thatat least one of X and Y is CH₂; R² and R³ are independently selectedfrom the group consisting of hydrogen, methyl, fluorine, and chlorine;and R⁴ is selected from the group consisting of

 where R⁵ and R⁶ are each independently selected from the groupconsisting of substituted and unsubstituted aryl and heteroaryl; or apharmaceutically acceptable salt, a pharmaceutically acceptable prodrug,or a pharmaceutically active metabolite thereof, or a pharmaceuticallyacceptable salt of said metabolite.
 8. A compound according to claim 7,wherein R⁵ and R⁶ are each independently selected from the groupconsisting of substituted and unsubstituted aryl; or a pharmaceuticallyacceptable salt, a pharmaceutically acceptable prodrug, or apharmaceutically active metabolite thereof, or a pharmaceuticallyacceptable salt of said metabolite.
 9. A compound according to claim 7,wherein R⁵ and R⁶ are each independently selected from the groupconsisting of substituted and unsubstituted heteroaryl; or apharmaceutically acceptable salt, a pharmaceutically acceptable prodrug,or a pharmaceutically active metabolite thereof, or a pharmaceuticallyacceptable salt of said metabolite.
 10. A compound according to claim 7,wherein: X is CH₂; Y is S; R² and R³ are independently selected from thegroup consisting of hydrogen, methyl, fluorine, and chlorine; and R⁴ isselected from the group consisting of

 where R⁵ and R⁶ are each independently selected from the groupconsisting of substituted and unsubstituted aryl and heteroaryl; or apharmaceutically acceptable salt, a pharmaceutically acceptable prodrug,or a pharmaceutically active metabolite thereof, or a pharmaceuticallyacceptable salt of said metabolite.
 11. A compound according to claim10, wherein R⁵ and R⁶ are each independently selected from the groupconsisting of substituted and unsubstituted aryl; or a pharmaceuticallyacceptable salt, a pharmaceutically acceptable prodrug, or apharmaceutically active metabolite thereof, or a pharmaceuticallyacceptable salt of said metabolite.
 12. A compound selected from thegroup consisting ofN-(3,4,5-Trimethoxyphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;N-(3,4,5-Trimethoxyphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide;N-(4-Isopropyl-3-methylphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;N-(4-Isopropyl-3-methylphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide;N-(4-Isopropyl-3-methylphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;N-(2-Methylquinolin-6-yl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;N-(3-Isopropylphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;N-(3,5-Dibromo-4-methylphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;N-(3,4,5-Trimethoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;N-(3,4,5-Trimethoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;N-(Quinolin-6-yl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanyl-methyl]benzamide;N-(5-Methylisoxazol-3-yl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;N-(Pyridin-4-yl)methyl-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;N-(1,3-Benzodioxyl-5-ylmethyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]benzamide;N-(2-Methoxybenzyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]benzamide;N-(2-Phenylethyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;N-(2-Methoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]benzamide;N-[3-(N-Methyl-N-phenylamino)propyl]-3-[(5-methyl-1H-1,2,4-triazol-3-yl)sulfanylmethyl]benzamide;N-(1,3-Benzodioxyl-5-ylmethyl)-3-[(5-methyl-1H-1,2,4-triazol-3-yl)sulfanylmethyl]benzamide;N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl-sulfanyl)methyl]benzamide;N-(3,3-Diphenylpropyl)-3-{[(5-methyl-1H-1,2,4-triazol-3-yl)-sulfanyl]methyl}benzamide;3-[(5-Methyl-1H-1,2,4-triazol-3-yl)-sulfonyl]methyl}-N-phenethylbenzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-isopropylphenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-trifluoromethyl-5-methoxyphenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3,5-bis-trifluoromethylphenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-t-butylphenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-isopropylphenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-trifluoromethoxyphenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3,5-dimethylphenyl)-benzamide:3[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-(2-hydroxyethyl)phenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-dimethylaminophenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-trifluoromethylsulfonylphenyl)-benzamide;3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-dimethylaminophenyl)-benzamide;3-[(5-Cyanoamino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]-N-(3,4,5-trimethoxyphenyl)benzamide;3-[(5-(Methoxycarbonylamino)-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]-N-(3,4,5-trimethoxyphenyl)benzamide;N-(3,4,5-Trimethoxyphenyl)-3-[(5-acetylamino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide;N-(4-Isopropyl-3-methylphenyl)-3-[(pyrazin-2-yl)methylsulfanyl]benzamide;N-(2-Methylquinolin-6-yl)-3-[(pyrazin-2-yl)methylsulfanyl]benzamide;N-(2-Methyl-quinolin-6-yl)-3-(pyridin-3-ylmethylsulfanyl)-benzamidedihydrochloride;N-(2-methyl-quinolin-6-yl)-3-[{5-(phenylamino)-2-H-pyrazol-3-yl}methylsulfanyl]benzamide;N-(3,4,5-trimethoxyphenyl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]benzamide;3-[{5-((E)-2-(4-Hydroxy-3-methoxyphenyl)ethenyl)-2H-pyrazol-3-yl}-methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide;3-[5-(2-(3,4-Dimethoxyphenyl)ethenyl)-2H-pyrazol-3-yl)methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide;3-(2-{5-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-2H-pyrazol-3-yl}-ethyl)-N-(3-methyl-4-isopropylphenyl)-benzamide;4-Fluoro-3-[{5-((E)-1-propenyl)-2H-pyrazol-3-yl}methoxy]-N-[4-(pyrrolidin-1-yl)-3-trifluoromethylphenyl]benzamide;3-(2-{5-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-2H-pyrazol-3-yl}-ethyl)-N-(3-methyl-4-isopropylphenyl)-benzamide;N-(4-Isopropyl-3-methyl-phenyl)-3-{2-[5-(4-(methylsulfamoyl)-phenylamino)-2H-pyrazol-3-yl]-ethyl}-benzamide;N-(2-Methylquinolin-6-yl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]benzamide;N-(4-isopropyl-3-methylphenyl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]benzamide;N-(4-Isopropyl-3-methyl-phenyl)-3-{2-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-benzamide;N-(4-Dimethylamino-3-trifluoromethylphenyl)-3-{2-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}-benzamide;N-(6-Dimethylamino-5-trifluoromethylpyridin-3-yl)-3-{2-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}-benzamide;N-(3,5-Dichloro-4-dimethylaminophenyl)-3-{2-[5-(6-methoxy-pyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}benzamide;3-{2-[5-(6-Methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-N-(4-pyrrolidin-1-yl-3-trifluoromethylphenyl)benzamide;3-{2-[5-(6-Methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-N-[4-(4-t-butoxycarbonylpiperazin-1-yl)-3-trifluoromethylphenyl]benzamide;3-{2-[5-(6-Methoxypyridin-3-yl)amino)-2H-pyrazol-3-yl]ethyl}-N-(4-piperazin-1-yl-3-trifluoromethylphenyl)benzamide;4-Fluoro-3-[{5-(pyridin-3-yl)amino-2H-pyrazol-3-yl}methoxy]-N-[((4-pyrrolidin-1-yl)-3-trifluoromethylphenyl)benzamide;N-(4-Isopropyl-3-methyl-phenyl)-3-[2-(5-phenylamino-2-H-pyrazol-3-yl)-cyclopropyl]-benzamide;3-[({3-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-5-yl}methyl)amino]-N-(3-methyl-4-isopropylphenyl)benzamide;3-[({5-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-3-yl}methyl)amino]-N-phenyl)benzamide;4-Fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-3-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-ylmethoxy]-benzamide;4-Fluoro-3-[5-(6-methoxy-pyridin-3-yl)amino-2H-pyrazol-3-yl]methoxy-N-(4-pyrrolidin-1-yl-3-trifluoromethyl-phenyl)-benzamide;4-Fluoro-3-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]methoxy-N-(3-methoxy-5-trifluoromethyl-phenyl)-benzamide;N-(4-Isopropyl-3-methyl-phenyl)-3-(Isoquinolin-4-yl)methoxy-benzamide;3-(Isoquinolin-4-yl)methoxy-N-(3,4,5-trimethoxyphenyl)benzamidehydrochloride;3-(Isoquinolin-4-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamidehydrochloride;3-(Isoquinolin-4-yl)methoxy-N-(2-methyl-4-methylsulfanyl-quinolin-6-yl)-benzamidehydrochloride;3-(Pyridin-3-yl)methoxy-N-(3,4,5-trimethoxyphenyl)benzamide;N-(Naphthalen-2-yl)-3-(pyridin-3-yl)methoxybenzamide;N-(1-Allyl-1H-indol-5-yl)-3-(pyridin-3-yl)methoxy-benzamide;3-(Pyridin-3-yl)methoxy-N-quinolin-6-yl-benzamide;N-(2-Methyl-quinolin-6-yl)-3-(pyridin-3-yl)methoxy-benzamide;N-(4-Isopropyl-3-methyl-phenyl)-4-fluoro-3-(Isoquinolin-4-yl)methoxy-benzamide;N-(4-Isopropyl-3-methyl-phenyl)-4-methyl-3-(Isoquinolin-4-yl)methoxy-benzamide;N-(4-Isopropyl-3-methyl-phenyl)-4-chloro-3-(Isoquinolin-4-yl)methoxy-benzamide;3-(6-Aminopyridin-3-yl)methoxy-N-(4-Isopropyl-3-methyl-phenyl)benzamide;3-(6-Aminopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide;3-(6-Acetylaminopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide;3-(6-Acetylaminopyridin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide;4-Fluoro-N-(1,2,3,4-tetrahydroquinolin-6-yl)-3-(isoquinolin-4-yl-methoxy)-benzamidebistrifluoroacetic acid salt;N-(2,2-difluorobenzo[1,3]dioxol-4-yl-ethyl)-benzamide trifluoroaceticacid salt;4-Fluoro-N-(2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(isoquinolin-4-yl-methoxy)-benzamidebistrifluoroacetic acid salt;N′-{4-[3-(4-Isopropyl-3-methyl-phenylcarbamoyl)-phenoxy;N-(4-Isopropyl-3-methyl-phenyl)-3-{1-[N′-(3-methoxy-benzylidene)-hydrazino]-isoquinolin-4-ylmethoxy}-benzamide;N-(3,5-Diallyl-4-methyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide;N-(3,5-Dibromo-4-methyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide;3-(Isoquinolin-4-ylmethoxy)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide;3-(Isoquinolin-4-ylmethoxy)-N-(3-trifluoromethoxy-phenyl)-benzamide;N-(2,4-Dimethylquinolin-6-yl)-3-(isoquinolin-4-ylmethoxy)-benzamide;3-(Isoquinolin-4-ylmethoxy)-benzoic acidN′-(4-trifluoromethyl-phenyl)-hydrazide;N-Benzyloxy-3-(isoquinolin-4-ylmethoxy)-benzamide;3-(Isoquinolin-4-ylmethoxy)-benzoic acid N′-phenyl-hydrazide;N-(5,7-dimethyl1,8]naphthydrin-2-yl)-3-(isoquinolin-4-ylmethoxy)-benzamide;3-(Isoquinolin-4-ylmethoxy)-N-(1,1,3,3-tetramethyl-1,3-dihydroisobenzofuran-5-yl)-benzamide;N-(3,5-Dichloro-4-pyrrolidin-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide;4-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(pyridin-3-ylmethoxy)-benzamide;4-Fluoro-N-[4-(piperazin-1-yl)-3-trifluoromethylphenyl-3-3-(pyridin-3-yl)methoxybenzamide;4-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide;4-Fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide;4-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(quinolin-3-ylmethoxy)-benzamide;4-Fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-3-(quinolin-3-ylmethoxy)-benzamide;N-(3,5-Dichloro-4-morpholin-4-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide;N-(3,5-Dichloro-4-piperazin-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide;4-Fluoro-N-[4-(piperazin-1-yl)-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide;4-Fluoro-N-(4-(imidazol-1-yl-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide;4-Fluoro-N-(4-pyrazol-1-yl-3-trifluoromethyl-phenyl)-3-(pyridin-3-ylmethoxy)-benzamide;4-Fluoro-3-(pyridin-3-ylmethoxy)-N-(4-[1,2,4]triazol-1-yl-3-trifluoromethyl-phenyl)-benzamide;N-(3,5-Dichloro-4-imidazol-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide;3-(5-Bromo-pyridin-3-ylmethoxy)-4-fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamide;3-(2-Isoquinolin-4-yl-ethyl)-N-phenyl-benzamide;3-(2-Isoquinolin-4-yl-ethyl)-N-(3,3,5-trimethyl-cyclohexyl)-benzamide;N-(4-Isopropyl-3-methyl-phenyl)-3-(2-isoquinolin-4-yl-ethyl)-benzamide;3-(2-Isoquinolin-4-yl-ethyl)-N-(2-methyl-quinolin-6-yl)-benzamide;N-(3,5-Dibromo-4-methyl-phenyl)-3-(2-isoquinolin-4-yl-ethyl)-benzamide;N-(4,6-Dimethyl-pyridin-2-yl)-3-(2-isoquinolin-4-yl-ethyl)-benzamide;2-Chloro-4-fluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide;2,4-Difluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide;2-Fluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide;N-(2-Methyl-quinolin-6-yl)-3-(2-pyridin-3-yl-ethyl)-benzamidehydrochloride;N-(4-Isopropyl-3-methyl-phenyl)-3-(2-pyridin-3-yl-ethyl)-benzamide;N-(3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-ylsulfanylmethyl]phenyl}-(3-bromo-4-methyl)benzamide;N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-ylsulfanylmethyl]phenyl}-3,5-bis(trifluoromethyl)benzamide;N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-hydroxy-3-methoxy)benzamide;N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-hydroxy-3-t-butyl)benzamide;N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-4-t-butylbenzamide;N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-phenoxy)benzamide;N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl]phenyl}-N′-[3,5-bis-(trifluoromethyl)phenyl]urea;N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl]phenyl}-N′-(pyridin-3-yl)urea;N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(3,5-di-t-butyl)benzamide;3-Bromo-4-hydroxy-N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-benzamide;N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-quinoline-6-carboxamide;5-Fluoro-N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-indole-2-carboxamide;N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-indole-6-carboxamide;(R/S)-2-(2-methylphenyl)-N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl)-methyl]phenyl}butanamide;3-t-Butyl-4-hydroxy-N-{3-[5-(6-methoxy-pyridin-3-ylamino)-2H-pyrazol-3-ylmethylsulfanyl]-phenyl}-benzamide;3-t-Butyl-4-hydroxy-N-[3-(pyridin-3-ylmethylsulfanyl)-phenyl}-benzamide;3-t-Butyl-4-hydroxy-N-[3-(isoquinolin-4-ylmethylsulfanyl)-phenyl}-benzamide;[3-(5-Bromo-pyridin-3-ylmethoxy)-phenyl]-3-t-butyl-4-hydroxy-benzamide;4-Acetoxy-3-t-butyl-N-[3-(pyridin-3-ylmethoxy)phenyl]-benzamide;4-Acetoxy-3-t-butyl-N-[3-(isoquinolin-4-ylmethoxy)phenyl]-benzamide;3-t-Butyl-4-hydroxy-N-[3-(pyridin-3-ylmethoxy)-phenyl]-benzamide;3-t-Butyl-4-hydroxy-N-[3-(isoquinolin-4-ylmethoxy)-phenyl]-benzamide;1-[3-(pyridin-3-ylmethoxy)phenylcarbamoyl]pyrrolidine;4-[3-(pyridin-3-ylmethoxy)phenylcarbamoyl]morpholine;3-[{6-Methoxy-7-(2-methoxyethoxy)cinnolin-4-yl}sulfanylmethyl]-N-phenyl-benzamide;3-[2-(6-Acetylamino-pyridin-3-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoro-methylphenyl)-benzamidedihydrochloride;3-[2-(6-Amino-pyridin-3-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride;3-[2-(3H-Imidazo[4,5-b]pyridin-6-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride;5-{2-[3-(Piperazin-1-yl-trifluoromethyl-phenylcarbamoyl)-phenyl]-ethyl}-nicotinamidedihydrochloride;5-{2-[3-(Piperazin-1-yl-trifluoromethyl-phenylcarbamoyl)-phenyl]-ethyl}-nicotinicacid methyl ester dihydrochloride;4-Fluoro-3-[2-(3H-imidazo[4,5-b]pyridin-6-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride; and4-Fluoro-3-(5-furan-2-yl-pyridin-3-ylmethoxy)-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamidedihydrochloride; or a pharmaceutically acceptable salt, pharmaceuticallyacceptable prodrug, or pharmaceutically active metabolite thereof or apharmaceutically acceptable salt of said metabolite.
 13. A compoundselected from the group consisting of the compounds corresponding toExample B-27 (Compounds 1-244), Example V-6d (Compounds 1-176), ExampleV-7b (Compounds 1-43) and Example V-14 (Compounds 1-88), or apharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically active metabolite thereof or a pharmaceuticallyacceptable salt of said metabolite.
 14. A pharmaceutically acceptablesalt of a pharmaceutically active metabolite of a compound according toclaim
 1. 15. A pharmaceutical composition for modulating or inhibitingthe activity of a protein kinase receptor comprising: (a) atherapeutically effective amount of an agent selected from the groupconsisting of a compound according to claim 1, a pharmaceuticallyacceptable prodrug thereof, a pharmaceutically active metabolitethereof, and a pharmaceutically acceptable salt thereof; and (b) apharmaceutically acceptable carrier, diluent, or vehicle therefor.
 16. Apharmaceutical composition for modulating or inhibiting the activity ofa protein kinase receptor comprising: (a) a therapeutically effectiveamount of a pharmaceutically acceptable salt of a pharmaceuticallyactive metabolite of a compound according to claim 1; (b) apharmaceutically acceptable carrier, diluent, or vehicle therefor.
 17. Amethod of treating a mammalian disease condition mediated by proteinkinase activity, comprising administering to a mammal in need thereof atherapeutically effective amount of an agent selected from the groupconsisting of a compound according to claim 1, a pharmaceuticallyacceptable prodrug thereof, a pharmaceutically active metabolitethereof, and a pharmaceutically acceptable salt thereof.
 18. A methodaccording to claim 17, wherein the mammalian disease condition isassociated with tumor growth, cell proliferation, or angiogenesis.
 19. Amethod of modulating or inhibiting the activity of a protein kinasereceptor, comprising contacting the kinase receptor with an effectiveamount of an agent selected from the group consisting of a compoundaccording to claim 1, a pharmaceutically acceptable prodrug thereof, apharmaceutically active metabolite thereof, and a pharmaceuticallyacceptable salt thereof.
 20. A method according to claim 19, wherein theprotein kinase receptor is a VEGF receptor.